Complement pathway modulators and uses thereof

7-Methyl-1H-indol-5-ol

Potassium nitrosodisulfonate (46.1 g, 172 mmol) was added to a 0.1 M aqueous solution of sodium phosphate at pH=7 (1 L) at room temperature. 7-Methylindoline (CAS #: 65673-86-1) (10.4 g, 78 mmol) was dissolved in 100 mL of acetone and added to the reaction in one portion at room temperature. After 30 minutes the reaction was diluted with ethyl acetate and the organic layer was separated. The aqueous layer was then extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The resulting residue was absorbed onto silica and then purified by silica gel flash chromatography (0-50% ethyl acetate in heptanes) to provide the title compound. MS (ESI+) m/z 148.08 (M+H).

5-(Allyloxy)-7-methyl-1H-indole

7-Methyl-1H-indol-5-ol (5.2 g, 35.3 mmol) was dissolved in toluene (221 mL) and prop-2-en-1-ol (2.42 mL, 35.3 mmol) was added followed by cyanomethylenetributylphosphorane (21.32 g, 88 mmol). The reaction was heated at 100° C. After 1 hour the reaction was cooled to room temperature, concentrated and purified by silica gel flash chromatography (0:100 EtOAc:heptanes) to provide the title compound. MS (ESI+) m/z 188.15 (M+H).

4-Allyl-7-methyl-1H-indol-5-ol

5-(Allyloxy)-7-methyl-1H-indole (2.02 g, 8.43 mmol) was heated neat at 230° C. for 6 min. The reaction was then cooled in an ice bath. The reaction was then dissolved in methanol and absorbed onto silica and then purified by silica gel flash chromatography (100% methylene chloride) to provide the title compound. MS (ESI+) m/z 188.11 (M+H).

tert-Butyl 4-allyl-5-hydroxy-7-methyl-1H-indole-1-carboxylate

To a solution of 4-allyl-7-methyl-1H-indol-5-ol (4.03 g, 21.52 mmol) in acetonitrile (26.9 mL) was added Boc 2 O (15 mL, 64.6 mmol) and DMAP (0.263 g, 2.15 mmol), and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated, then diluted with MeOH (75 mL) and K 2 CO 3 (14.87 g, 108 mmol) was added. After 3 hours the reaction was neutralized with AcOH (6 mL). Water was then added and the layers were separated. The aqueous layer was extracted with EtOAc. The organics layer was washed with brine, dried over MgSO 4 , filtered and concentrated. The product was purified by silica gel flash chromatography (0-50% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 288.2 (M+H).

tert-Butyl 4-allyl-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate

tert-Butyl 4-allyl-5-hydroxy-7-methyl-1H-indole-1-carboxylate (3.6 g, 12.53 mmol) was dissolved in acetonitrile (62.6 mL) and water (62.6 mL), then KOH (14.06 g, 251 mmol) was added and the solution was stirred until all the KOH went into solution. The resulting solution was then cooled to −78° C. (solution froze) and diethyl bromodifluoromethylphosphonate (4.45 mL, 25.06 mmol) was added. The reaction was removed from the dry ice bath and allowed to warm to room temperature. After 1 hour, EtOAc and water were added, and the resulting layers were separated. The aqueous layer was further extracted with EtOAc. The combined organics were washed with brine, dried over MgSO 4 , filtered and concentrated. The resulting residue was purified by flash chromatography (0-40% EtOAc in heptanes) to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.69 (d, J=3.79 Hz, 1H) 7.08 (t, J=74.7 Hz, 1H) 6.96 (s, 1H) 6.76 (d, J=3.79 Hz, 1H) 5.89 (dd, J=16.93, 10.36 Hz, 1H) 4.91-5.05 (m, 2H) 3.57 (d, J=6.32 Hz, 2H) 1.59 (s, 9H). MS (ESI+) m/z 338.1 (M+H).

tert-Butyl 5-(difluoromethoxy)-7-methyl-4-(prop-1-en-1-yl)-1H-indole-1-carboxylate

To solution of tert-butyl 4-allyl-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (2.05 g, 6.08 mmol) in 1,1,1,3,3,3-hexafluoroisopropanol (7.6 mL) was added Pd(OAc) 2 (0.041 g, 0.182 mmol) and the reaction stirred for 45 minutes at room temperature. At this point the reaction was concentrated and purified directly by flash chromatography (0-40% EtOAc in heptanes) to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.71 (d, J=4.04 Hz, 1H) 6.87-7.32 (m, 3H) 6.65 (dd, J=16.17, 1.77 Hz, 1H) 6.26-6.43 (m, 1H) 1.94 (dd, J=6.69, 1.64 Hz, 3H) 1.60 (s, 9H).

tert-Butyl 5-(difluoromethoxy)-4-formyl-7-methyl-1H-indole-1-carboxylate

To a solution of tert-butyl 5-(difluoromethoxy)-7-methyl-4-(prop-1-en-1-yl)-1H-indole-1-carboxylate (1.83 g, 5.42 mmol) in dioxane (40 mL) and water (13.56 mL) at 0° C., 2,6-lutidine (1.26 mL, 10.85 mmol), OsO 4 (1.36 mL, 0.108 mmol) (2.5% in t-BuOH) and NaIO 4 (4.64 g, 21.70 mmol) were added and the reaction was stirred at room temperature. After 1 hour the reaction was diluted with DCM and the layers separated. The organics were washed with sat. NH 4 Cl and water, dried over MgSO 4 , filtered and concentrated. The resulting residue was purified by flash chromatography (0-40% EtOAc in heptanes) to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.45 (s, 1H) 7.93 (d, J=3.54 Hz, 1H) 7.37 (d, J=3.54 Hz, 1H) 7.34 (t, J=73.6 Hz, 1H) 7.16 (s, 1H) 2.63 (s, 3H) 1.61 (s, 9H). MS (ESI+) m/z 326.2 (M+H).

1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of 1H-benzo[d]imidazole-5-carbonitrile (CAS#; 6287-83-8) (1 g, 3.81 mmol) in DMF (50 mL) was added NaH (60% in mineral oil, 610 mg, 15.3 mmol), and then the mixture was stirred at room temperature for 1 hr, and then cooled down to 0° C. SEMCl (0.75 mL, 4.2 mmol) was then added at 0° C., and then the mixture was stirred at 0° C. for 0.5 h. The reaction was quenched with MeOH at 0° C. and then diluted with Et 2 O. The layers were separated and the organic layer was washed successively with H 2 O and brine, it was then dried over Na 2 SO 4 , filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (10-20% EtOAc in DCM) to give the title compounds as a mixture, which was used as is. MS (ESI+) m/z 274.3 (M+H).

(±)-tert-Butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate

To a solution of a mixture of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (2.25 g, 8.24 mmol) in THF (34.0 mL), LDA (2.0M in heptane/THF/ethylbenzene, 3.71 mL, 7.41 mmol) was added at −78° C. After stirring for 30 min., a solution of tert-butyl 5-(difluoromethoxy)-4-formyl-7-methyl-1H-indole-1-carboxylate (1.34 g, 4.12 mmol) in THF (8 mL) was added to the reaction mixture. After stirring for 15 minutes, the reaction mixture was diluted with MeOH (12 mL), sat. aq. NH 4 Cl (60 mL), sat. aq. brine (60 mL) and EtOAc (200 mL). The layers were separated and the aqueous layer was extracted twice with EtOAc. The organic layer was washed with brine, dried over MgSO 4 , filtered, and concentrated. The resulting residue was purified by flash column chromatography (0-60% EtOAc in heptanes) to provide the mixture of title compounds. MS (ESI+) m/z 599.5 (M+H).

a) (±)-2-((5-(Difluoromethoxy)-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(((2-aminoethyl)amino)(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of a mixture of tert-butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (600 mg, 1 mmol) in THF (10.0 mL), ethylenediamine (0.67 mL, 10 mmol) was added followed by TBAF (1M in THF, 10.0 mL, 10 mmol) and the reaction was stirred overnight at 55° C. The reaction was then cooled to room temperature, quenched with sat. aq. NH 4 Cl, extracted with EtOAc, and the organic extract was dried over MgSO 4 , filtered and concentrated. The resulting residue was purified by flash chromatography (0-80% EtOAc in heptanes, then 0-30% (10% NH 4 OH in MeOH-DCM) to provide two products in the following order.

(±)-2-((5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 13.05 (br. s., 1H) 11.17 (br. s., 1H) 7.91 (s, 1H) 7.59 (br. s., 1H) 7.50 (br. s., 1H) 7.27 (t, J=2.40 Hz, 1H) 7.11 (dd, J=78.06, 73.77 Hz, 1H) 6.80 (s, 1H) 6.59 (d, J=4.04 Hz, 1H) 6.51 (d, J=4.04 Hz, 1H) 6.37-6.47 (m, 1H) 2.46 (s, 3H). HRMS calcd. for C 19 H 14 F 2 N 4 O 2 (M+H) + 369.1158. found 369.1169.

(±)-2-(((2-aminoethyl)amino)(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.19 (br. s., 1H) 7.84-8.02 (m, 1H) 7.59 (d, J=8.34 Hz, 1H) 7.47 (dd, J=8.34, 1.52 Hz, 1H) 7.28 (d, J=2.53 Hz, 1H) 7.06 (t, J=75.5 Hz, 1H) 6.80 (s, 1H) 6.50 (d, J=2.78 Hz, 1H) 5.66 (s, 1H) 2.53-2.73 (m, 4H) 2.46 (s, 3H). HRMS calcd. for C 21 H 20 F 2 N 6 O (M+H) + 411.174. found 411.1755.

b) (+) and (−)-2-((5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-((5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral HPLC using a CHIRALPAK® IC column with 30% IPA and 0.2% DEA in Heptanes to give (−)-2-((5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =6.87 min) and (+)-2-((5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =11.76 min).

(±)-2-((5-(Difluoromethoxy)-7-methyl-1H-indol-4-yl)(methylamino)methyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of a mixture of tert-butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (20 mg, 0.033 mmol) and methylamine (2.0M in THF, 0.17 mL, 0.33 mmol) in THF (0.33 mL) at room temperature, TBAF (1M in THF, 0.33 mL, 0.33 mmol) was added and the mixture was stirred at 55° C. After stirring overnight the reaction was cooled to room temperature, quenched with sat. aq. NH 4 Cl, extracted with EtOAc, and the organic extract was dried over MgSO 4 , filtered and concentrated. The resulting residue was purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.22 (br. s., 1H) 7.94 (br. s., 1H) 7.60 (d, J=8.34 Hz, 1H) 7.49 (dd, J=8.34, 1.52 Hz, 1H) 7.29 (t, J=2.78 Hz, 1H) 7.06 (t, J=75.5 Hz, 1H) 6.81 (s, 1H) 6.49 (dd, J=3.03, 2.02 Hz, 1H) 5.55 (s, 1H) 2.46 (d, J=0.76 Hz, 3H) 2.36 (s, 3H). HRMS calcd. for C 20 H 17 F 2 N 5 O (M+H) + 382.1474. found 382.1489.

tert-Butyl 4-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and tert-butyl 4-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate

To a solution of a mixture of (±)-tert-butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (Example 3-A) (700 mg, 1.169 mmol) in DCM (16.7 mL), manganese dioxide (1016 mg, 11.69 mmol) was added and the reaction was stirred at room temperature. After stirring overnight additional manganese dioxide (508 mg) was added. After an additional 2 hours the solid was filtered through a pad of Celite®, washed with DCM, and the filtrate was concentrated. The resulting residue was purified by flash chromatography (0-40% EtOAc in heptanes) to provide the mixture of title compounds. MS (ESI+) m/z 597.5 (M+H).

(±)-tert-Butyl 4-(((tert-butylsulfinyl)imino)(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(((tert-butylsulfinyl)imino)(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate

A mixture of tert-butyl 4-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and tert-butyl 4-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (0.41 g, 0.69 mmol), (±)-2-methylpropanesulfinamide (0.092 g, 0.76 mmol) and Ti(OiPr) 4 (1.4 mL, 4.81 mmol) were stirred at 90° C. After 90 minutes the reaction mixture was cooled to room temperature and diluted with EtOAc and sat. aq. brine. The resulting mixture was filtered and the organic layer of the filtrate was dried over MgSO 4 , filtered, and concentrated. The resulting residue was purified by flash chromatography (0-50% EtOAc in heptanes) to provide a mixture of title compounds. MS (ESI+) m/z 700.6 (M+H).

(±)-tert-Butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)ethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)ethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate

To a solution of a mixture of (±)-tert-butyl 4-(((tert-butylsulfinyl)imino)(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(((tert-butylsulfinyl)imino)(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (349 mg, 0.499 mmol) in THF (5 mL), MeMgCl (3M in THF, 0.5 mL, 1.49 mmol) was added at 0° C. After 10 minutes the mixture was diluted with sat. aq. NH 4 Cl and EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO 4 , filtered and concentrated. The resulting residue was purified by flash chromatography (0-100% EtOAc in heptanes) to provide a mixture of the title compounds. MS (ESI+) m/z 716.5 (M+H).

(±)-tert-Butyl 4-(1-amino-1-(5-cyano-1H-benzo[d]imidazol-2-yl)ethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate

To a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)ethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)ethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (306 mg, 0.427 mmol) was added HCl (1.25M in MeOH, 1.7 mL, 2.137 mmol) and the solution was stirred at room temperature for 90 minutes. The reaction mixture was then concentrated, diluted with sat. aq. NaHCO 3 , the aqueous layer was extracted with EtOAc, and the organic extract was dried over MgSO 4 , filtered and concentrated. The residue was purified by flash chromatography (0-80% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 482.3 (M+H).

a) (±)-2-(1-Amino-1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of tert-butyl 4-(1-amino-1-(5-cyano-1H-benzo[d]imidazol-2-yl)ethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (77 mg, 0.160 mmol) in MeOH (1.6 mL) at room temperature, Cs 2 CO 3 (261 mg, 0.8 mmol) was added and the reaction was stirred at 60° C. After 1 hour the reaction mixture was loaded directly onto a silica gel column and purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.19 (br. s., 1H) 7.96 (br. s., 1H) 7.58 (br. s., 1H) 7.50 (dd, J=8.21, 1.39 Hz, 1H) 7.28 (t, J=2.91 Hz, 1H) 6.70 (s, 1H) 6.66 (t, J=75.3 Hz, 1H) 6.45 (br. s., 1H) 2.45 (d, J=0.76 Hz, 3H) 2.00 (s, 3H). HRMS calcd. for C 20 H 17 F 2 N 5 O (M+H) + 382.1474. found 382.1486.

b) (+) and (−)-2-(1-amino-1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(1-amino-1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[c]imidazole-5-carbonitrile was achieved by chiral SFC using a CHIRALPAK®AD-H column with 25% IPA+0.2% DEA in CO 2 to give (+)-2-(1-amino-1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =2.6 min) and (−)-2-(1-amino-1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile=3.3 min).

(±)-tert-Butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxy ethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate

To a solution of a mixture of tert-butyl 4-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and tert-butyl 4-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (Example 5-A) (0.67 g, 1.12 mmol) in THF (11.23 mL) at −78° C., MeMgBr (1.0 M in butyl ether, 1.68 mL, 1.68 mmol) was added and the reaction was stirred at −78° C. After 10 minutes additional MeMgBr (1.0 M in butyl ether, 0.28 mL, 0.28 mmol) was added. After another 10 minutes the reaction was quenched with sat. aq. NH 4 Cl and brine, the layers were separated and the aqueous layer was extracted with EtOAc, and the organic extract was dried over MgSO 4 , filtered and concentrated. The resulting residue was purified by flash chromatography (0-70% EtOAc in heptanes) to provide a mixture of the title compounds. MS (ESI+) m/z 613.6 (M+H).

a) (±)-2-(1-(5-(Difluoromethoxy)-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (310 mg, 0.504 mmol) in THF (5 mL) at room temperature, ethylenediamine (0.34 mL, 5.04 mmol) was added followed by TBAF (1M in THF, 5.04 mL, 5.04 mmol) and the reaction was stirred at 60° C. After 2 days the reaction was cooled to room temperature, quenched with sat. aq. WWI and extracted with EtOAc. The organic layers were combined, dried over MgSO 4 , filtered and concentrated. The resulting residue was purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.51 (s, 1H) 11.12 (br. s., 1H) 8.06 (m) 7.81 (m) 7.65-7.74 (m) 7.46-7.56 (m) 7.29 (t, J=2.78 Hz, 1H) 6.72 (br. s., 1H) 6.68 (s, 1H) 6.65 (t, J=75.8 Hz, 1H) 6.22 (s, 1H) 2.45 (s, 3H) 2.09 (s, 3H). HRMS calcd. for C 20 H 16 F 2 N 4 O 2 (M+H) + 383.1314. found 383.1321.

b) (+) and (−)-2-(1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral HPLC using a CHIRALPAK® AD column with 25% EtOH (−)-0.2% DEA) in heptanes to give (−)-2-(1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =6.55 min) and (+)-2-(1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =8.52 min).

(+) or (−)-2-(1-(3-chloro-5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of (+)-2-(1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile (32 mg, 0.083 mmol) in DMF (0.83 mL) was added NCS (17 mg, 0.12 mmol) at 0° C., and the reaction was warmed to room temperature. After 2 hours the reaction was quenched with sat. aq. Na 2 S 2 O 3 and extracted with EtOAc. The organic extract was dried over MgSO 4 , filtered and concentrated. The resulting residue was purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.51-12.66 (m, 1H) 11.56 (br. s., 1H) 8.04 (m) 7.79-7.83 (m) 7.64-7.70 (m) 7.44-7.56 (m) 6.83-6.89 (m) 6.75 (s, 1H) 6.64-6.70 (m) 6.46-6.51 (m) 6.07-6.20 (m, 1H) 2.45 (s, 3H) 2.18 (s, 3H). HRMS calcd. for C 20 H 15 ClF 2 N 4 O 2 (M+H) + 417.0925. found 417.0942.

(±)-tert-Butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-methoxyethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-methoxyethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate

To a solution of a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (605 mg, 0.987 mmol) in DMF (9.9 mL) at 0° C., NaH (60% in mineral oil, 59 mg, 1.5 mmol) was added followed by MeI (0.12 mL, 1.98 mmol). After stirring overnight the reaction was quenched with sat. aq. NH 4 Cl and extracted with EtOAc. The organic extract was dried over MgSO 4 , filtered and concentrated. The resulting residues was purified by flash chromatography (0-50% EtOAc in heptanes) to provide a mixture of the title compounds. MS (ESI+) m/z 627.6 (M+H).

a) (±)-2-(1-(5-(Difluoromethoxy)-7-methyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-methoxyethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-methoxyethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (475 mg, 0.758 mmol) in THF (7.6 mL) at room temperature, ethylenediamine (0.51 mL, 7.58 mmol) was added followed by TBAF (1M in THF, 7.6 mL, 7.6 mmol) and the reaction was stirred at 60° C. After 6 hours the reaction was cooled to room temperature, additional ethylenediamine (0.51 mL, 7.58 mmol) and TBAF (1M in THF, 7.6 mL, 7.6 mmol) were added and the reaction was stirred at 60° C. overnight. The reaction was cooled to room temperature, quenched with NH 4 Cl and extracted with EtOAc. The organic extract was dried over MgSO 4 , filtered and concentrated. The resulting residue was purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.68-12.85 (m, 1H) 11.19 (br. s., 1H) 8.09 (m) 7.83 (m) 7.69-7.74 (m) 7.47-7.58 (m) 7.31 (t, J=2.78 Hz, 1H) 6.89-6.96 (m) 6.70-6.77 (m) 6.46-6.58 (m) 3.01-3.17 (m, 3H) 2.46 (s, 3H) 2.07 (s, 3H). HRMS calcd. for C 21 H 18 F 2 N 4 O 2 (M+H) + 397.1471. found 397.1482.

b) (+) and (−)-2-(1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a CHIRALPAK® AD column with 25% MeOH in CO 2 to give (+)-2-(1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =1.6 min) and (−)-2-(1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =3.4 min).

4-Methyl-2-(methylthio)-5-nitrobenzonitrile

To a solution of 2-bromo-4-methyl-5-nitrobenzonitrile (3 g, 12.45 mmol) in DMF (124 mL), sodium thiomethoxide (1.31 g, 18.67 mmol) was added and the reaction heated to 60° C. for 1 h. The reaction was then cooled to room temperature, quenched with a sat. aq. solution of NaHCO 3 and extracted with EtOAc. The organic extract was dried over MgSO 4 , filtered and concentrated. The resulting residue was purified using FCC eluting with heptanes:EtOAc 1:1 to give the title compound. MS (ESI−) m/z 207.3 (M−H).

7-Methyl-5-(methylthio)-1H-indole-4-carbonitrile

To a solution of 4-methyl-2-(methylthio)-5-nitrobenzonitrile (1.6 g, 7.68 mmol) in THF (80 mL) at −78° C. under nitrogen, was added rapidly 1M vinylmagnesium bromide in THF (30.7 mL, 30.7 mmol). After addition was complete, the reaction was stirred at −78° C. for 30 min. The reaction was then quenched with sat. aq. NH 4 Cl and extracted with EtOAc. The organic extract was dried over MgSO 4 , filtered and concentrated. The pure title compound was isolated using FCC (0-50% EtOAc in heptanes). MS (ESI−) m/z 201.2 (M−H).

7-Methyl-5-(methylthio)-1-tosyl-1H-indole-4-carbonitrile

To a solution of 7-methyl-5-(methylthio)-1H-indole-4-carbonitrile (500 mg, 2.47 mmol) in DMF (20 mL), was added NaH (60% in mineral oil, 148 mg, 3.71 mmol) and p-toluenenesulfonyl chloride (707 mg, 3.71 mmol). The reaction mixture was stirred at rt for 2 h, at which time additional NaH (60% in mineral oil, 148 mg, 3.71 mmol) and p-toluenenesulfonyl chloride (707 mg, 3.71 mmol) were added. After an additional 1 h of stirring the reaction mixture was then quenched with sat. aq. NH 4 Cl and extracted with EtOAc. The organic extract was dried over MgSO 4 , filtered and concentrated. The resulting residue was purified using FCC (0-20% EtOAc in heptanes) to afford the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.10 (d, J=3.79 Hz, 1H) 7.63-7.69 (m, 2H) 7.43 (m, 2H) 7.21 (s, 1H) 6.90 (d, J=3.79 Hz, 1H) 2.59 (s, 3H) 2.56 (d, J=0.76 Hz, 3H) 2.37 (s, 3H).

7-Methyl-5-(methylthio)-1-tosyl-1H-indole-4-carbaldehyde

To a solution of 7-methyl-5-(methylthio)-1-tosyl-1H-indole-4-carbonitrile (560 mg, 1.57 mmol) in toluene (15 mL) at −78° C., DIBAL-H (2 mL, 2 mmol) was added. After 30 minutes, a 3 N aq. HCl solution (50 mL) was added and the reaction warmed to rt and left stirring for 30 minutes. The organics were extracted with DCM, dried and concentrated. The pure title compound was isolated using FCC (0-50% EtOAc in heptanes). MS (ESI+) m/z 360.2 (M+H).

(±)-2-(Hydroxy(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and (±)-2-(hydroxy(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

The reaction was conducted as described in Example 3-A starting from 7-methyl-5-(methylthio)-1-tosyl-1H-indole-4-carbaldehyde. MS (ESI+) m/z 633.5 (M+H).

(±)-2-(Hydroxy(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and (±)-2-(hydroxy(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

A stock solution of ammonium molibdate tetrahydrate (240 mg, 0.19 mmol) in 50% w/v aqueous peroxide (0.6 mL) was prepared at 0° C. To a solution of a mixture of (±)-2-(hydroxy(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and (±)-2-(hydroxy(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (100 mg, 0.158 mmol) in EtOH (2 mL), at 0° C., 0.16 mL of the above stock solution were added and the reaction allowed to reach rt. After 2 h the reaction mixture was then diluted with water (4 mL) and extracted with EtOAc. The organic extract was dried over MgSO 4 , filtered and concentrated. The resulting residue was purified using FCC eluting with heptane:EtOAc 1:1 to give a mixture of the two title compounds. MS (ESI+) m/z 665.5 (M+H).

(±)-2-(Hydroxy(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

To a mixture of (±)-2-(hydroxy(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and (±)-2-(hydroxy(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (100 mg, 0.150 mmol) was added a 1 M solution of lithium tetrafluoroborate in MeCN (3.0 mL, 3 mmol). Water (0.3 mL) was then added and the reaction heated to 70° C. overnight. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic extract was dried over MgSO 4 , filtered and concentrated. The resulting residue was dissolved in EtOH (1.3 mL) and isomylamine (0.3 mL, 2.6 mmol) and KOH (0.072 g, 1.3 mmol) were added. The mixture was then heated to 100° C. for 1 h using microwave irradiation. The mixture was then concentrated directly and purified using FCC eluting with DCM:MeOH:NH 4 OH 100:0:0 to 80:18:2 to give the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.17 (br. s., 1H), 11.50 (br. s., 1H), 7.83-8.00 (m, 1H), 7.61-7.67 (m, 1H), 7.49-7.58 (m, 2H), 7.41-7.49 (m, 1H), 7.35 (q, J=2.40 Hz, 1H), 6.91 (dd, J=4.67, 7.58 Hz, 1H), 6.58 (dt, J=1.89, 3.66 Hz, 1H), 3.46 (m, 3H), 2.53 (s, 3H). HRMS calcd. for C 19 H 16 N 4 O 3 S (M+H) + 381.1021. found 381.1013.

2-(7-Methyl-5-(methylthio)-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 2-(7-methyl-5-(methylthio)-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of a mixture of (±)-2-(hydroxy(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and (±)-2-(hydroxy(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (330 mg, 0.521 mmol) in DCM (5 mL), Dess-Martin Periodinane (332 mg, 0.782 mmol) was added. After 30 min the reaction was quenched with saturated aq. NaHCO 3 and 50% aq. sodium thiosulfate. The mixture was extracted with DCM and the organic extract was dried over MgSO 4 , filtered and concentrated. The resulting residue was purified using FCC eluting with heptane:EtOAc 1:1 to give a mixture of the title compounds. MS (ESI+) m/z 631.4 (M+H).

(±)-2-(1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and (±)-2-(1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of a mixture of 2-(7-methyl-5-(methylthio)-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 2-(7-methyl-5-(methylthio)-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (330 mg, 0.52 mmol) in THF (5 mL) at −78° C., was added methylmagnesium iodide (0.35 mL, 1.05 mmol). After 20 minutes of stirring the reaction was quenched with sat. aq. NH 4 Cl and extracted with EtOAc. The organic extract was dried over MgSO 4 , filtered and concentrated. The resulting residue was purified using FCC eluting with heptane:EtOAc 1:1 to give a mixture of the title compounds. MS (ESI+) m/z 647.5 (M+H).

a) (±)-2-(1-hydroxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

A mixture of (±)-2-(1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and (±)-2-(1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile was transformed into the title compound using the same reaction conditions as described in Example 10-B and Example 10-C. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.24-12.49 (m, 1H), 11.46 (br. s., 1H), 8.17-8.32 (m), 7.70-7.84 (m, 2H), 7.54 (m, 1H), 7.45 (m), 7.18 (t, J=2.91 Hz, 1H), 6.49-6.69 (m, 1H), 5.63 (dt, J=1.83, 3.82 Hz, 1H), 3.55 (s, 3H), 2.51 (s, 3H), 2.27 (s, 3H). HRMS calcd. for C 20 H 18 N 4 O 3 S (M+H) + 395.1173. found 395.1173.

b) (+) and (−)-2-(1-hydroxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(1-hydroxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a CHIRALPAK®AD-H column with 20% MeOH in CO 2 to give (+) or (−)-2-(1-hydroxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =3 min) and (−) or (+)-2-(1-hydroxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =4.2 min).

(±)-2-(1-Methoxy-1-(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and (±)-2-(1-methoxy-1-(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of a mixture of (±)-2-(1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and (±)-2-(1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (Example 11-B) (0.54 g, 0.835 mmol) in DMF (8.35 mL) at 0° C. was added MeI (0.08 mL, 1.25 mmol) and 60% NaH in mineral oil (0.050 g, 1.25 mmol). After stirring for 1 h the reaction was quenched with a sat. aq. solution of NH 4 Cl and extracted with EtOAc. The organic extract was dried over MgSO 4 , filtered and concentrated. The resulting residue was dissolved in EtOH (5 mL) and placed at 0° C. 0.6 mL of an ammonium molibdate tetradydrate stock solution [ammonium molibdate tetradydrate (240 mg, 0.19 mmol) in 50% w/v aqueous peroxide (0.6 mL) prepared at 0° C.] was added and the reaction allowed to warm to rt. It was then diluted with water and extracted with EtOAc. The organic extract was dried over MgSO 4 , filtered and concentrated. The resulting residue was purified using FCC eluting with DCM/MeOH 95:5 to give a mixture of the title compounds. MS (ESI+) m/z 693.4 (M+H).

a) (±)-2-(1-Methoxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

A mixture of (±)-2-(1-methoxy-1-(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and (±)-2-(1-methoxy-1-(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile was transformed into the title compound using the same reaction conditions as described in Example 10-C. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.51-12.55 (m, 1H), 11.48 (br. s., 1H), 8.32-8.33 (m), 7.80-7.98 (m, 2H), 7.56-7.61 (m), 7.42-7.44 (m), 7.18 (t, J=2.91 Hz, 1H), 5.3 (br. s., 1H), 3.41 (s, 3H), 3.05 (s, 3H), 2.18 (s, 3H). MS (ESI+) m/z 409.1 (M+H).

b) (+) and (−)-2-(1-methoxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(1-methoxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a Lux® Cellulose-2 column with 25% MeOH in CO 2 to give (+) or (−)-2-(1-methoxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =3.5 min) and (−) or (+)-2-(1-methoxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =6.1 min).

(±)-N-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)methylene)-2-methylpropane-2-sulfinamide and (±)-N-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)methylene)-2-methylpropane-2-sulfinamide

A mixture of 2-(7-methyl-5-(methylthio)-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 2-(7-methyl-5-(methylthio)-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (Example 11-A) (600 mg, 0.951 mmol), 2-methylpropanesulfinamide (127 mg, 1.046 mmol) and Ti(OiPr) 4 (2 mL, 6.7 mmol) was stirred at 90° C. After 20 minutes the reaction mixture was cooled to room temperature and diluted with EtOAc and brine. The resulting mixture was filtered and the organic layer of the filtrate was dried over MgSO 4 , filtered, and concentrated. The resulting residue was purified by flash chromatography (0-60% EtOAc in heptanes) to give a mixture of the title compounds. MS (ESI+) m/z 734.6 (M+).

(±)-N-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide and (±)-N-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of a mixture of (±)-N-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)methylene)-2-methylpropane-2-sulfinamide and (±)-N-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)methylene)-2-methylpropane-2-sulfinamide (590 mg, 0.804 mmol) in THF (8 mL) at 0° C. was added methylmagnesium iodide (0.8 mL, 2.41 mmol). After 10 minutes the mixture was diluted with a saturated aq. solution of NH 4 Cl and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were dried over MgSO 4 , filtered and concentrated. The resulting residue was purified by flash chromatography (0-100% EtOAc in heptanes) to give a mixture of the title compounds. MS (ESI+) m/z 750.5 (M+).

(±)-2-(1-Amino-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

To a mixture of (±)-N-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide and (±)-N-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide (0.63 g, 0.840 mmol), was added 1.25 M HCl in MeOH (14.00 mL, 16.80 mmol) and the reaction mixture was then heated to 60° C. for 2 h. The reaction mixture was then evaporated directly, basified with ammonium hydroxide and directly loaded onto silica gel and purified by FCC and eluted with heptane/EtOAc 1:1 to give the title compound. MS (ESI−) m/z 514.2 (M−1).

(±)-2-(1-Amino-1-(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

(±)-2-(1-Amino-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile was transformed into the title compound using the same reaction conditions as described in Example 10-B. MS (ESI+) m/z 548.2 (M+H).

a) (±)-2-(1-Amino-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of (±)-2-(1-amino-1-(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[c]imidazole-5-carbonitrile (0.550 g, 1 mmol) in EtOH (10 mL), sodium ethoxide (22% solution in EtOH) (5.94 g, 20.09 mmol) was added and the reaction heated to 60° C. for 1 h. The mixture was then evaporated and directly purified using FCC eluting with heptane:EtOAc 100:0 to 0:100 to give the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.20 (br. s., 1H), 11.42 (br. s., 1H), 8.19 (m), 7.79-7.91 (m), 7.47-7.62 (m), 7.34-7.47 (m), 7.18 (m, 1H), 5.72 (br. s., 1H), 3.73 (s, 3H), 3.14 (s, 3H), 2.18 (s, 3H). HRMS calcd. for C 20 H 19 N 5 O 2 S (M+H) + 394.1332. found 394.1334.

b) (+) and (−)-2-(1-Amino-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(1-amino-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[c]imidazole-5-carbonitrile was achieved by chiral SFC using CHIRALCEL® OJ-H column with 10% MeOH (−)-0.2% DEA) in CO 2 (due to miscibility issues of this compound a (21×50 mm) AD column in front of OJ-H was used as mixer) to give (+)-2-(1-amino-1-(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =8.2 min) and (−)-2-(1-amino-1-(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =11 min).

(±)-2-(2,2,2-Trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

To a solution of a mixture of 2-(7-methyl-5-(methylthio)-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(7-methyl-5-(methylthio)-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 11-A) (1.98 g, 3.14 mmol) in THF (31.4 mL) at 0° C. was added trifluoromethyltrimethylsilane (4.90 mL, 31.4 mmol), then TBAF (1M in THF, 31.4 mL, 31.4 mmol) was added and the mixture was warmed to room temperature. After 10 minutes the reaction was diluted with water, extracted with EtOAc, and the organic extract was dried over MgSO 4 , filtered and concentrated. The resulting residue was purified by flash chromatography (0-60% EtOAc in heptanes) to afford the mixture of the title compounds. MS (ESI+) m/z 701.3 (M+H).

(±)-2-(2,2,2-Trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

To a mixture of (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (246 mg, 0.351 mmol) was added HCl (1.25M in MeOH, 2.8 mL, 3.51 mmol) and the mixture was stirred at 60° C. After 30 minutes the reaction was cooled to room temperature, concentrated and basified with aq. NH 4 OH. The mixture was further diluted with MeOH. The resulting residue was purified directly by flash chromatography (0-80% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 571.1 (M+H).

(±)-2-(2,2,2-Trifluoro-1-hydroxy-1-(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

A stock solution of ammonium molybdate tetrahydrate (240 mg, 0.19 mmol) in 50% w/v aqueous hydrogen peroxide (0.6 mL) was prepared. To a solution of (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (191 mg, 0.335 mmol) in EtOH (2.8 mL), at 0° C., 0.6 mL of the molybdate stock solution was added and the reaction allowed to reach room temperature. After 45 minutes the reaction was diluted with water, extracted with EtOAc, and the organic extract was dried over MgSO 4 , filtered and concentrated. The product was purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 603.0 (M+H).

a) (±)-2-(2,2,2-Trifluoro-1-hydroxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of 2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (187 mg, 0.310 mmol) in EtOH (3103 μL) was added sodium ethoxide (21% in EtOH, 2.3 mL, 6.21 mmol) and the mixture was stirred at 60° C. After 2 hours the reaction was cooled to room temperature and stirred overnight. The mixture was concentrated and then purified directly by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.64-12.79 (m, 1H) 11.60 (br. s., 1H) 8.38-8.49 (m) 8.05 (s, 1H) 7.97-8.03 (m) 7.89 (m) 7.58-7.66 (m, 1H) 7.48-7.55 (m) 7.18-7.32 (m, 1H) 5.61 (br. s., 1H) 3.52 (s, 3H) 2.57 (s, 3H). HRMS calcd. for C 20 H 16 F 3 N 4 O 3 S (M+H) + 449.0895. found 449.0889.

b) (+) and (−)-2-(2,2,2-Trifluoro-1-hydroxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral HPLC using a Lux® Cellulose-2 column with 20% EtOH in heptanes to give (+)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =11.44 min) and (−)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =14.44 min).

(±)-2-(2,2,2-Trifluoro-1-methoxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(2,2,2-trifluoro-1-methoxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

To a solution of a mixture of (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 14-A) (300 mg, 0.428 mmol) in DMF (4.3 mL) at 0° C., MeI (0.27 mL, 4.28 mmol) was added followed by NaH (60% in mineral oil, 34.2 mg, 0.856 mmol). After 5 minutes the mixture was warmed to room temperature. After 15 minutes the reaction was quenched with sat. aq. NH 4 Cl, extracted with EtOAc, and the organic extract was dried over MgSO 4 , filtered and concentrated. The resulting residues was purified by flash chromatography (0-50% EtOAc in heptanes) to provide a mixture of the title compounds. MS (ESI+) m/z 715.4 (M+H).

(±)-2-(2,2,2-Trifluoro-1-methoxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

To a mixture of (±)-2-(2,2,2-trifluoro-1-methoxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(2,2,2-trifluoro-1-methoxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (265 mg, 0.371 mmol) was added HCl (1.25M in MeOH, 2.9 mL, 3.71 mmol) and the mixture was stirred at 60° C. After 20 minutes the reaction was cooled to room temperature, concentrated and basified with aq. NH 4 OH. The mixture was further diluted with MeOH. The resulting residue was purified directly by flash chromatography (0-80% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 585.1 (M+H).

(±)-2-(2,2,2-Trifluoro-1-methoxy-1-(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

A stock solution of ammonium molybdate tetrahydrate (240 mg, 0.19 mmol) in 50% w/v aqueous hydrogen peroxide (0.6 mL) was prepared. To a solution of (±)-2-(2,2,2-trifluoro-1-methoxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (223 mg, 0.381 mmol) in EtOH (3.2 mL), at 0° C., 0.6 mL of the molybdate stock solution was added and the reaction was allowed to reach room temperature. After 70 minutes an additional aliquot of the ammonium molybdate stock solution (0.3 mL) was added. After another 65 minutes an additional aliquot of the ammonium molybdate stock solution (0.3 mL) was added. After a total of 5 hours, the reaction was diluted with water, extracted with EtOAc, and the organic extract was dried over MgSO 4 , filtered and concentrated. The product was purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 617.1 (M+H).

a) (±)-2-(2,2,2-Trifluoro-1-methoxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

To (±)-2-(2,2,2-trifluoro-1-methoxy-1-(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (172 mg, 0.279 mmol) in EtOH (2.8 mL) was added sodium ethoxide (21% in EtOH, 2 mL, 5.58 mmol) and the mixture was stirred at 60° C. After 45 minutes the reaction was cooled to room temperature and purified directly by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.84-13.00 (m, 1H) 11.59 (br. s., 1H) 8.47 (m) 8.00-8.19 (m) 7.94 (m) 7.61-7.72 (m, 1H) 7.50-7.61 (m) 7.27 (br. s., 1H) 5.45 (br. s., 1H) 3.39 (br. s., 3H) 3.21 (br. s., 3H) 2.57 (s, 3H). HRMS calcd. for C 21 H 17 F 3 N 4 O 3 S (M+H) + 463.1052. found 463.1031.

b) (+) and (−)-2-(2,2,2-trifluoro-1-methoxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(2,2,2-trifluoro-1-methoxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a Lux® Cellulose-2 column with 20-30% MeOH (5 mM NH 3 OH) in CO 2 to give (+)-2-(2,2,2-trifluoro-1-methoxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =2.8 min) and (−)-2-(2,2,2-trifluoro-1-methoxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =3.5 min).

(±)-2-(2,2,2-Trifluoro-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

To a mixture of (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 14-A) (0.37 g, 0.528 mmol) was added HCl (1.25M in MeOH, 4.22 mL, 5.28 mmol) and the mixture was stirred at 60° C. After 40 minutes the mixture was cooled to room temperature and concentrated. The residue was dissolved in CHCl 3 (10.56 mL), and thionyl chloride (0.385 mL, 5.28 mmol) and a few drops of DMF were added and the mixture was heated at 70° C. After 2 hours the reaction was cooled to room temperature and concentrated. The residue was dissolved in methylamine (33% in EtOH, 6.57 mL, 52.8 mmol) and stirred at room temperature. After 5 minutes the reaction was concentrated and purified directly by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 584.2 (M+H).

a) (±)-2-(2,2,2-Trifluoro-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

(±)-2-(2,2,2-Trifluoro-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile was transformed into the title compound using the same procedure as described in Example 14-C and Example 14-D. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.60-12.75 (m, 1H) 11.55 (br. s., 1H) 8.42 (m) 7.98-8.09 (m) 7.84-7.92 (m) 7.57-7.66 (m, 1H) 7.46-7.54 (m) 7.22 (t, J=3.03 Hz, 1H) 5.61 (br. s., 1H) 5.04 (br. s., 1H) 3.65 (s, 3H) 2.56 (s, 3H) 2.04 (d, J=4.04 Hz, 3H). HRMS calcd. for C 21 H 18 F 3 N 5 O 2 S (M+H) + 462.1212. found 462.1198.

b) (+) and (−)-2-(2,2,2-trifluoro-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(2,2,2-trifluoro-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a Lux® Cellulose-2 column with 17-27% MeOH in CO 2 to give (+)-2-(2,2,2-trifluoro-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =3.6 min) and (−)-2-(2,2,2-trifluoro-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =4.4 min).

(±)-2-(1-Amino-2,2,2-trifluoro-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

To a mixture of (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 14-A) (425 mg, 0.6 mmol) was added HCl (1.25M in MeOH, 4.85 mL, 6.06 mmol) and the mixture was stirred at 60° C. After 40 minutes the mixture was cooled to room temperature and concentrated. The mixture was dissolved in CHCl 3 (12 mL), then was added thionyl chloride (0.44 mL, 6.06 mmol) and one drop of DMF and the mixture was heated at 70° C. After 4 hours the reaction was cooled to room temperature and stirred at room temperature overnight. The reaction was then concentrated, dissolved in ammonia in ethanol (2.0M, 30.3 mL, 60.6 mmol) and stirred at room temperature. After 15 minutes the reaction was concentrated and purified directly by flash chromatography (0-70% EtOAc in heptanes). MS (ESI+) m/z 570.3 (M+H).

a) (±)-2-(1-Amino-2,2,2-trifluoro-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

(±)-2-(1-Aamino-2,2,2-trifluoro-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile was transformed into the title compound using the same procedures as described in Example 14-C and Example 14-D. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.47-12.64 (m, 1H) 11.55 (br. s., 1H) 8.37-8.41 (m) 8.00-8.02 (m, 1H) 7.96-8.00 (m) 7.83-7.85 (m) 7.56-7.63 (m, 1H) 7.45-7.49 (m) 7.15-7.27 (m, 1H) 5.54-5.71 (m, 1H) 4.12 (s, 2H) 3.74 (s, 3H) 2.56 (s, 3H). HRMS calcd. for C 20 H 16 F 3 N 5 O 2 S (M+H) + 448.105. found 448.1058.

b) (+) and (−)-2-(1-amino-2,2,2-trifluoro-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(1-amino-2,2,2-trifluoro-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a CHIRALPAK® AD-H column with 25% MeOH+0.2% DEA in CO 2 to give (−)-2-(1-amino-2,2,2-trifluoro-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =1.7 min) and (+)-2-(1-amino-2,2,2-trifluoro-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =4.0 min).

(±)-N-((6-Cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)methyl)-2-methylpropane-2-sulfinamide and (±)-N-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)methyl)-2-methylpropane-2-sulfinamide

To a solution of a mixture of (±)-N-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)methylene)-2-methylpropane-2-sulfinamide and (±)-N-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)methylene)-2-methylpropane-2-sulfinamide (Example 13-A) (1.2 g, 1.63 mmol) in MeOH (15 mL), sodium borohydride (0.37 g, 9.81 mmol) was added at 0° C. After 30 minutes the reaction was complete. It was then quenched with sat. aq. NH 4 Cl solution and extracted with EtOAc. The organic extract was dried over MgSO 4 filtered and concentrated. The resulting residue was purified using FCC eluting with heptanes:EtOAc 1:1 to give the mixture of title compounds. MS (ESI+) m/z 737.8 (M+H).

(±)-2-(amino(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of a mixture of (±)-N-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)methyl)-2-methylpropane-2-sulfinamide and (±)-N-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)methyl)-2-methylpropane-2-sulfinamide (1 g, 1.36 mmol), HCl in methanol (1.25 M) (22 mL, 27 mmol) was added and the reaction stirred at 60° C. for 2 h. The reaction was then evaporated, basified with NH 4 OH (33% NH 3 in H 2 O) and extracted with EtOAc. The organic extract was dried over MgSO 4 filtered and concentrated to give the title compound without the need for further purification. MS (ESI+) m/z 502.2 (M+H).

(±)-2-(amino(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

A stock solution of ammonium molibdate tetrahydrate (480 mg, 0.19 mmol) in 50% w/v aqueous peroxide (1.2 mL) was prepared at 0° C. To a solution of (±)-2-(amino(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (400 mg, 0.797 mmol) in EtOH (5 mL), at 0° C., 1.2 mL of the above stock solution was added and the reaction warmed to room temperature and stirred for 2 h. The mixture was then diluted with water, extracted with EtOAc. The organic extract was dried over MgSO 4 filtered and concentrated. The resulting residue was purified using FCC eluting with DCM/MeOH 95:5 to give the title compound. MS (ESI+) m/z 534.3 (M+H).

(+) and (−)-2-(amino(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of (±)-2-(amino(7-methyl-5-(methylsulfonyl)-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (540 mg, 1.012 mmol) in EtOH (10 mL), a 21% solution of sodium ethoxide (7.6 mL, 20.24 mmol) was added and the reaction heated to 60° C. for 1 h. The reaction was cooled to room temperature and then evaporated directly. It was partially purified via FCC eluting with DCM:MeOH 95:5. The product of this purification was further purified using chiral HPLC using an AD column eluting with 45% IPA (0.2% DEA) in heptane to give (+)-2-((5,7-dimethyl-3-(pyridin-3-yl)-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =5.4 min) and (−)-2-((5,7-dimethyl-3-(pyridin-3-yl)-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =8.7 min). 1 H NMR (HCl salt, 400 MHz, DMSO-d 6 ) δ 11.56 (br. s., 1H), 7.94 (s, 1H), 7.53-7.68 (m, 2H), 7.50 (dd, J=1.39, 8.34 Hz, 1H), 7.16-7.39 (m, 1H), 6.63 (s, 1H), 6.25 (dd, J=1.71, 3.09 Hz, 1H), 3.37 (s, 3H), 2.53 (d, J=0.76 Hz, 3H). HRMS calcd. for C 19 H 17 N 5 O 2 S (M+H) + , 380.1181. found 380.1184.

4-Allyl-5-methoxy-7-methyl-1H-indole

4-Allyl-7-methyl-1H-indol-5-ol (Example 1-C) (2.77 g, 14.79 mmol) was dissolved in toluene (74.0 mL) and methanol (0.599 mL, 14.79 mmol) was added followed by cyanomethylenetributylphosphorane (8.93 g, 37.0 mmol). The reaction was heated at 110° C. for 1 hour. The reaction was cooled to room temperature and then concentrated. The residue was then absorbed onto silica and purified by silica gel flash chromatography (0-50% ethyl acetate/heptanes) to provide the title compound. MS (ESI+) m/z 202.17 (M+H).

tert-Butyl 4-allyl-5-methoxy-7-methyl-1H-indole-1-carboxylate

4-Allyl-5-methoxy-7-methyl-1H-indole (6.4 g, 31.8 mmol) was dissolved in acetonitrile (106 mL) and then Boc 2 O (11.07 mL, 47.7 mmol) was added followed by DMAP (0.039 g, 0.318 mmol). The reaction was then stirred at room temperature overnight. The reaction was concentrated and absorbed onto silica and then purified by silica gel flash chromatography (0-50% ethyl acetate/heptanes) to provide the title compound. MS (ESI+) m/z 302.19 (M+H).

tert-Butyl 5-methoxy-7-methyl-4-(prop-1-en-1-yl)-1H-indole-1-carboxylate

To a solution of tert-Butyl 4-allyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (9.8 g, 32.5 mmol) in 1,1,1,3,3,3-hexafluoro-propanol (HFIPA) (40.6 mL) was added to palladium(II) acetate (0.073 g, 0.325 mmol) in 4 mL of HFIPA. The reaction was stirred at room temperature for 4 hours. The reaction was concentrated and absorbed onto silica and then purified by silica gel flash chromatography (0-30% ethyl acetate/heptanes) to provide the title compound. MS (ESI+) m/z 302.25 (M+H).

tert-Butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate

tert-Butyl 5-methoxy-7-methyl-4-(prop-1-en-1-yl)-1H-indole-1-carboxylate (0.29 g, 0.97 mmol) was dissolved in dioxane (7.27 mL) and water (2.4 mL) and 2,6-lutidine (0.23 mL, 1.94 mmol) was added followed by osmium tetroxide (0.24 mL, 0.019 mmol) and sodium periodate (0.83 g, 3.88 mmol) at 0° C. The reaction was removed from the ice bath and let stir at room temperature for 1 hour. The reaction was diluted with methylene chloride and water. The organic layer was separated, dried over sodium sulfate and then concentrated. The resulting residue was absorbed onto silica and then purified by silica gel flash chromatography (0-50% ethyl acetate/heptanes) to provide the title compound. MS (ESI+) m/z 290.1 (M+H).

The following compounds are prepared with similar methods as described in Example 19 using the appropriate alcohol in place of MeOH in Example 19-A.

tert-Butyl 4-(2,2-dibromovinyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

To a solution of tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (902 mg, 3.12 mmol) in CH 2 Cl 2 (30 mL), CBr 4 (1.55 g, 4.68 mmol) was added at 0° C. followed by PPh 3 (2.45 g, 9.35 mmol). The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated and directly purified via FCC eluting with Heptane/DCM 100:0 to 0:100 to provide the title compound. MS (ESI+) m/z 446.0, 448.0, 444.0, 446.9 (M+H).

tert-Butyl 4-((5-cyano-1H-benzo[d]imidazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

A mixture of tert-butyl 4-(2,2-dibromovinyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (1.3 g, 2.92 mmol), 3,4-diaminobenzonitrile (700 mg, 5.26 mmol) and DABCO (819 mg, 7.30 mmol) in NMP (12 mL) was stirred at 110° C. for overnight. The reaction mixture was then cooled to room temperature, diluted with EtOAc, and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified using FCC eluting with heptane/EtOAc(60-80%) to provide the title compound. MS (ESI+) m/z 417.2 (M+H).

2-((5-Methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of tert-butyl 4-((5-cyano-1H-benzo[d]imidazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (878 mg, 2.108 mmol) in THF (12 mL) and MeOH (12 mL) was added Cs 2 CO 3 (3.4 g, 10.54 mmol). The mixture was stirred at 58° C. for 1 hour. The reaction mixture was cooled to room temperature, concentrated and purified by flash chromatography (DCM:EtOAc) to provide the title compound. 1 H NMR (400 MHz, DICHLOROMETHANE-d 2 ) δ ppm 8.24 (br. s., 1H) 7.86 (s, 1H) 7.59 (d, J=8.34 Hz, 1H) 7.46-7.54 (m, 1H) 7.30 (t, J=2.91 Hz, 1H) 6.87 (s, 1H) 6.71 (m, 1H) 4.60 (s, 2H) 4.03 (s, 3H) 2.53 (s, 3H). HRMS calcd. for C 13 H 16 N 4 O (M+H) + 317.1397. found 317.1400.

The following compounds were prepared with a similar method as described above using aldehydes in Example 19.

tert-Butyl 4-allyl-7-fluoro-5-methoxy-1H-indole-1-carboxylate

The title compound was synthesized from 7-fluoroindoline using the same procedure as described in Example 1-A to 1-C and 19-A to 19-B. 1 H NMR (400 MHz, DICHLOROMETHANE-d 2 ) δ ppm 7.60 (d, J=3.79 Hz, 1H) 6.72 (d, J=14.15 Hz, 1H) 6.56 (dd, J=3.79, 2.02 Hz, 1H) 5.87-6.01 (m, 1H) 4.90-4.98 (m, 2H) 3.83 (s, 3H) 3.54 (dt, J=6.19, 1.58 Hz, 2H) 1.62 (s, 9H).

2-((7-Fluoro-5-methoxy-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

A vial was charged with tert-butyl 4-allyl-7-fluoro-5-methoxy-1H-indole-1-carboxylate (60 mg, 0.196 mmol) and dioxane/water (3:1, total volume=2 mL). The mixture was charged with 2,6-lutidine (0.046 mL, 0.393 mmol) and cooled to 0° C. Osmium tetroxide (2.5 wt % solution in t-BuOH, 0.049 mmol) was added, followed by sodium periodate (168 mg, 0.786 mmol). The reaction was stirred at 0° C. for 10 min and then warmed to room temperature. The heterogeneous reaction was quenched with a 1:1 mixture of aq. saturated ammonium chloride/sodium thiosulfate. The reaction mixture was then extracted with DCM and separated via phase separation cartridge. The organic layer was evaporated to dryness. The resulting residue was dissolved in THF (2 mL), t-BuOH (0.7 mL), and water (0.3 mL). To this mixture was added 2-methyl-2-butene (1.33 mL, 2.66 mmol) as a 2M solution in THF. The reaction was then charged with NaH 2 PO 4 (138 mg, 1 mmol) as a solid, cooled to 0° C., then sodium chlorite (90 mg, 1 mmol) was added as a solid. The reaction was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was diluted with a pH=7 buffer solution and extracted with EtOAc. The organic extract was dried over magnesium sulfate, filtered and evaporated. The resulting residue (69 mg, 0.213 mmol) was dissolved in DCM (3 mL). DIPEA (0.056 mL, 0.32 mmol), 3,4-diaminobenzonitrile (34 mg, 0.256 mmol) and HATU (97 mg, 0.256 mmol) were added to the mixture and the reaction was allowed to stir overnight at room temperature. The reaction was diluted with water and the layers were partitioned. The aqueous layer was extracted twice with DCM. The organic layer was separated by a phase separation cartridge (Isolute®) and concentrated to dryness. The crude material was (60 mg, 0.143 mmol) was dissolved in 2 mL 1:1 THF/MeOH and treated with solid cesium carbonate (139 mg, 0.428 mmol). The mixture was stirred for 2 h at room temperature and then purified by reverse phase preparative HPLC (HC-B) to afford the title compound. 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.83 (s, 1H) 7.54-7.60 (m, 1H) 7.46-7.48 (m, 1H) 7.25 (d, J=3.28 Hz, 1H) 6.81 (d, J=12.63 Hz, 1H) 6.42 (t, J=3.28 Hz, 1H) 4.49 (s, 2H) 3.84 (s, 3H). HRMS calcd. for C 18 H 13 FN 4 O (M+H) + 321.1152. found 321.1144.

2-((7-Chloro-5-( 2 H 3 )methoxy-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

The compound was synthesized using the same procedures as described in Example 19 and Example 21 starting from 7-chloroindoline and replacing MeOH with CD 3 OD when reproducing Example 19-A. 1 H NMR (400 MHz, DICHLOROMETHANE-d 2 ) δ ppm 9.60 (br. s., 1H) 7.81 (s, 1H) 7.48-7.56 (m, 1H) 7.37-7.46 (m, 1H) 7.22-7.31 (m, 1H) 6.99 (s, 1H) 6.57 (dd, J=3.16, 2.15 Hz, 1H) 4.50 (s, 2H). HRMS calcd. for C 18 H 10 ClD 3 N 4 O (M+H) + 340.1041. found 340.1033.

(±)-2-((5-((1-Methoxypropan-2-yl)oxy)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

The compound was synthesized using the same procedures as described in Example 19 and Example 21 starting from 7-methylindoline and replacing MeOH with (±)-1-methoxy-2-propanol when reproducing Example 19-A. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.97 (br. s., 1H) 7.91 (br. s., 1H) 7.51-7.58 (m, 1H) 7.46 (dd, J=8.08, 1.52 Hz, 1H) 7.22 (t, J=2.78 Hz, 1H) 6.77 (s, 1H) 6.21 (dd, J=3.03, 2.02 Hz, 1H) 4.29-4.47 (m, 2H) 3.39-3.49 (m, 1H) 3.33-3.37 (m, 2H) 3.22 (s, 3H) 2.44 (s, 3H) 1.13 (d, J=6.32 Hz, 3H). HRMS calcd. for C 22 H 22 N 4 O 2 (M+H) + 375.1816. found 375.1823.

(±)-tert-Butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

To a solution of a mixture of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (0.111 g, 0.409 mmol) in THF (1 mL), LDA (2 M in heptane/THF/ethylbenzene, 0.188 mL, 0.376 mmol) was added at −78° C. After stirring for 30 minutes tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 19-D) (0.103 g, 0.358 mmol) in THF (2 mL) was added at −78° C. and stirred at the same temperature for 3 hours. The reaction was quenched with MeOH (1 mL) and aq. NH 4 Cl (15 mL) and then diluted with EtOAc (40 mL). The layers were separated and the water layer was extracted twice with EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated and purified by flash chromatography (40 g, 0-40% ethyl acetate in heptanes) to provide a mixture of the title compounds. MS (ESI+) m/z 563.36 (M+H).

a) (±)-2-(Hydroxy(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

A mixture of (±)-tert-butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (0.3 g, 0.533 mmol) was dissolved in THF (5.33 mL). TBAF (5.34 mL, 5.34 mmol) was added to the solution and the reaction was stirred at 50° C. for 5 hours. The reaction was diluted with ethyl acetate and then with 20 mL of a saturated aq. solution of ammonium chloride. The ethyl acetate layer was separated, washed with water, dried and concentrated. The resulting residue was dissolved in MeOH (4 mL) to which cesium carbonate (0.87 g, 2.67 mmol) was added. The reaction was heated at 50° C. for 1 hour. The reaction was then concentrated and directly purified by flash chromatography (0-10% MeOH in DCM) to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.93 (d, J=3.54 Hz, 1H) 10.86 (br. s., 1H) 7.81-7.95 (m, 1H) 7.60 (m) 7.40-7.56 (m) 7.14 (t, J=2.78 Hz, 1H) 6.75 (s, 1H) 6.53-6.62 (m, 1H) 6.19-6.31 (m, 2H) 3.81 (s, 3H) 2.40-2.47 (m, 3H). HRMS calcd. for C 19 H 16 N 4 O 2 (M+H) + 333.1346. found 333.1355.

b) (+) and (−)-2-(hydroxy(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(hydroxy(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile is achieved by chiral HPLC using a CHIRALPAK® AD-H column with 30% ethanol (0.2% DEA) in heptane to give (+)-2-(hydroxy(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =5.4 min) and (−)-2-(hydroxy(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =9.3 min).

The following compounds were prepared with similar method.

tert-Butyl 4-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and tert-butyl 4-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

A mixture of (±)-tert-butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 24-A) (64 mg, 0.114 mmol) was dissolved in DCM (1.2 mL). MnO 2 (99 mg, 1.137 mmol) was added and stirred at room temperature for 18 hours. The mixture was filtered through a pad of Celite® and concentrated to obtain the mixture of title compounds without the need of further purification. MS (ESI+) m/z 561.36 (M+H).

2-(5-Methoxy-7-methyl-1H-indole-4-carbonyl)-1H-benzo[d]imidazole-5-carbonitrile

A mixture of tert-butyl 4-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and tert-butyl 4-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (62 mg, 0.11 mmol) was dissolved in THF (1.1 mL) and then TBAF (1.1 mL, 1.1 mmol) was added and the reaction was heated at 65° C. for 17 hours. The mixture was then cooled to room temperature and treated with 10 mL of a saturated aq. solution of ammonium chloride and then diluted with EtOAc. The organic layer was separated and washed with water (3×100 mL). The organic extract was dried over magnesium sulfate and concentrated. The resulting residue was dissolved in MeOH (4 mL), cesium carbonate (48.9 mg, 0.15 mmol) was added and the reaction was heated at 60° C. for 1 h. The reaction was cooled to room temperature, a saturated aq. solution of ammonium chloride was added, followed by EtOAc. The organic layer was separated, washed with water and the organic extracts combined, dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by flash column chromatography (0-40% EtOAc in heptanes) to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 13.73 (br. s., 1H) 11.33 (br. s., 1H) 8.29 (br. s.) 8.07 (br. s.) 7.60-7.90 (m, 2H) 7.45 (t, J=2.78 Hz, 1H) 6.89 (s, 1H) 6.42 (br. s., 1H) 3.56 (s, 3H) 2.54-2.63 (m, 3H). HRMS calcd. for C 19 H 14 N 4 O 2 (M+H) + 331.119. found 331.1202.

(±)-tert-Butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

A mixture of tert-butyl 4-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and tert-butyl 4-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (1.9 g, 3.39 mmol) was dissolved in tetrahydrofuran (33.9 mL) and then cooled to 0° C. in an ice bath. Methylmagnesium chloride (3M, 1.35 mL, 4.07 mmol) was added and the mixture was stirred at 0° C. for 30 minutes. The reaction was then quenched with 15 mL aq. NH 4 Cl and brine. The layers were separated and the aqueous layer was extracted with EtOAc. The organic extracts were combined, dried over Na 2 SO 4 , filtered, concentrated, and purified by flash chromatography (0-40% ethyl acetate in heptanes) to provide the mixture of title compounds. MS (ESI+) m/z 577.53 (M+H).

(±)-tert-Butyl 5-(benzyloxy)-4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 5-(benzyloxy)-4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-7-methyl-1H-indole-1-carboxylate

The mixture of title compounds was synthesized in a similar manner as described in Example 24, 25 and 26, starting from tert-butyl 5-(benzyloxy)-4-formyl-7-methyl-1H-indole-1-carboxylate (Example 19-H). MS (ESI+) m/z 653.2 (M+H).

a) (±)-2-(1-Hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

(±)-tert-Butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate was converted in the title compound using the same procedure described in Example 24-B. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.30 (s, 1H) 10.86 (br. s., 1H) 8.10 (s) 7.63-7.84 (m) 7.38-7.55 (m, 2H) 7.21 (q, J=3.12 Hz, 1H) 6.47-6.77 (m, 1H) 6.00 (d, J=1.01 Hz, 1H) 3.26-3.30 (m, 3H) 2.40-2.45 (m, 3H) 2.03 (s, 3H). HRMS calcd. for C 20 H 18 N 4 O 2 (M+H) + 347.1508. found 347.1510.

b) (+) and (−)-2-(1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile is achieved by chiral HPLC using a CHIRALPAK® AD-H column with 30% ethanol (0.2% DEA) in heptanes to give (−)-2-(1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =4.65 min) and (+)-2-(1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile=9.61 min).

The following compounds were prepared with similar method.

(±)-tert-Butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-methoxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-methoxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

To a solution of a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxy ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 26-A) (0.82 g, 1.42 mmol) in DMF (14.22 mL) was added NaH (60%, 0.074 g, 1.85 mmol) at 0° C. The ice bath was removed and the reaction was allowed to stir at room temperature for 10 minutes. The reaction was then placed back in the ice bath and MeI (0.116 mL, 1.85 mmol) was added. After 10 minutes, additional NaH (60%, 50 mg) and MeI (0.1 mL) were added and the ice bath was removed. After 15 minutes the reaction mixture was quenched with 15 mL of a saturated solution of aq. ammonium chloride and then diluted with ethyl acetate. The layers were separated and the organic layer was removed and washed with water. The organic extract was then dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography (0-40% ethyl acetate in heptanes) to provide the mixture of title compounds. MS (ESI+) m/z 591.52 (M+H).

a) (±)-2-(1-Methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

To a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-methoxy ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-methoxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (0.494 g, 0.836 mmol) in tetrahydrofuran (8.36 mL) was added TBAF (1M in THF, 8.36 mL, 8.36 mmol) and ethylenediamine (0.28 mL, 4.18 mmol). The reaction was heated at 65° C. for 26 hours. The reaction was cooled to room temperature and treated with 10 mL of a saturated solution of aq. ammonium chloride and then diluted with ethyl acetate. The layers were separated and the organic layer was washed with water (3×100 mL), dried over magnesium sulfate and concentrated. The resulting residue was dissolved in MeOH and cesium carbonate (1.38 g, 4.25 mmol) was added and the reaction was heated at 60° C. for 1.5 hours. The reaction was cooled to room temperature, diluted with EtOAc and then washed with a saturated solution of aq. ammonium chloride. The organic extract was dried over magnesium sulfate, filtered and concentrated. The resulting residues was purified by flash chromatography (0-10% MeOH in DCM) to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 with about 5 μL TFA) δ ppm 11.14 (br. s., 1H) 8.23 (s, 1H) 7.66-8.01 (m, 2H) 7.39 (t, J=2.91 Hz, 1H) 6.48-6.88 (m, 2H) 3.28 (s, 3H) 3.17 (s, 3H) 2.48 (s, 3H) 2.13 (s, 3H). HRMS calcd. for C 21 H 20 N 4 O 2 (M+H) + 361.1659. found 361.1675.

b) (+) and (−)-2-(1-methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(1-methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a CHIRALPAK® AD-H column with 25% MeOH in CO 2 to give (−)-2-(1-methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =0.93 min) and (+)-2-(1-methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =1.58 min).

The following compounds were prepared with similar method.

(±)-2-(Hydroxy(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(hydroxy(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

A mixture of (±)-tert-butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 24-A) (1.01 g, 1.80 mmol) was dissolved in MeOH (9 mL) and then Cs 2 CO 3 (2.94 g, 9.01 mmol) was added and the reaction was heated at 60° C. for 1 hour. The reaction was cooled to room temperature and then diluted with a saturated aq. solution of ammonium chloride, diluted with EtOAc and then washed with water. The organic extract was dried over magnesium sulfate, filtered, concentrated, and absorbed onto silica and purified by flash chromatography (0-10% MeOH in DCM) to provide the mixture of title compounds. MS (ESI+) m/z 463.41 (M+H).

(±)-2-((3-Chloro-5-methoxy-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((3-chloro-5-methoxy-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

A mixture of (±)-2-(hydroxy(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(hydroxy(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (0.67 g, 1.448 mmol) was dissolved in DMF (14.48 mL), and cooled to −15° C. NCS (0.24 g, 1.74 mmol) was then added. The ice bath was removed and the reaction was stirred for 2 hours at room temperature. The reaction was quenched with a saturated aq. solution of sodium thiosulfate and extracted with ethyl acetate. The organics layers were combined, dried over magnesium sulfate, filtered, concentrated and purified by flash chromatography (0-60% Ethyl acetate in heptanes) to provide the title compounds as a mixture. MS (ESI+) m/z 497.3 (M+H).

a) (±)-2-((3-Chloro-5-methoxy-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

A mixture of (±)-2-((3-chloro-5-methoxy-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((3-chloro-5-methoxy-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (0.2 g, 0.402 mmol) was dissolved in THF (4.02 mL) and treated with TBAF (1M in THF, 4.02 mL, 4.02 mmol) and ethylenediamine (0.272 mL, 4.02 mmol) and heated at 60° C. The reaction was cooled to room temperature, and treated with 10 mL of a saturated aq. solution of ammonium chloride and then diluted with EtOAc. The layers were separated and the organic layer was washed with water (3×100 mL). The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified via FCC (0-100% EtOAc in heptanes) to obtain the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.71 (d, J=6.57 Hz, 1H) 11.28 (br. s., 1H) 7.87 (d, J=6.19 Hz, 1H) 7.61 (m) 7.40-7.50 (m, 2H) 6.94-7.12 (m, 1H) 6.79 (s, 1H) 6.02-6.20 (m, 1H) 3.42-3.50 (m, 3H) 2.45 (s, 3H). HRMS calcd. for C 19 H 16 ClN 4 O 2 (M+H) + 367.0957. found 367.096.

b) (+) and (−)-2-((3-chloro-5-methoxy-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

Resolution of the enantiomers of 2-((3-chloro-5-methoxy-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile is achieved by chiral SFC using a CHIRALPAK® AD-H column with 35% MeOH in CO 2 to give (+)-2-((3-chloro-5-methoxy-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =1.8 min) and (−)-2-((3-chloro-5-methoxy-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =2.5 min).

(−) or (+)-2-(1-(3-Chloro-5-methoxy-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of (−)-2-(1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (Example 26-C) (20 mg, 0.058 mmol) in DMF (0.58 mL) was added NCS (14 mg, 0.1 mmol) at 0° C. The reaction was stirred in the ice bath for 1 hour. At this point, the reaction was quenched with a saturated solution of aq. Na 2 S 2 O 3 at 0° C., and then the mixture was extracted with EtOAc and then the EtOAc layer was dried, concentrated, absorbed onto silica and purified by flash column chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.18-12.43 (m, 1H) 11.29 (br. s., 1H) 8.06 (s) 7.65-7.79 (m) 7.45-7.52 (m) 7.43 (d, J=3.03 Hz, 1H) 6.72 (s, 1H) 5.78-6.09 (m, 1H) 3.16 (s, 3H) 2.42 (s, 3H) 2.15 (s, 3H). HRMS calcd. for C 20 H 17 ClN 4 O 2 (M+H) + 381.1113. found 381.1123.

(+) or (−)-2-(1-(3-chloro-5-methoxy-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from (+)-2-(1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (Example 26-C) in the same manner as described in Example 29-A. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.12-12.46 (m, 1H) 11.29 (br. s., 1H) 8.06 (s) 7.62-7.85 (m) 7.25-7.56 (m, 2H) 6.72 (s, 1H) 5.87-6.05 (m, 1H) 3.16 (s, 3H) 2.42 (s, 3H) 2.15 (s, 3H). HRMS calcd. for C 20 H 17 ClN 4 O 2 (M+H) + 381.1113. found 381.1127.

(±)-tert-Butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(methoxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(methoxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

To a solution of a mixture of (±)-tert-butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 24-A) (498 mg, 0.885 mmol) in DMF (2.5 mL) at 0° C. was added successively MeI (0.17 mL, 2.65 mmol) and NaH (60%, 53.1 mg, 1.32 mmol). The reaction mixture was stirred at 0° C. for 20 min. At this point, the reaction was quenched with a saturated aq. solution of NH 4 Cl, then diluted with water and extracted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 , filtered, concentrated and absorbed onto silica and purified by flash column chromatography (0-30% heptane in ethyl acetate) to provide a mixture of title compounds. MS (ESI+) m/z 577.37 (M+H).

(±)-2-(Methoxy(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from a mixture of (±)-tert-butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(methoxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate as described in Example 24-B. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.91 (d, J=6.57 Hz, 1H) 10.92 (br. s., 1H) 7.91-7.97 (m) 7.88 (m) 7.55-7.66 (m, 1H) 7.42-7.54 (m, 1H) 7.18 (t, J=2.72 Hz, 1H) 6.78 (s, 1H) 6.24-6.30 (m, 2H) 3.80 (s, 3H) 3.33 (s, 3H) 2.46 (s, 3H). HRMS calcd. for C 20 H 18 N 4 O 2 (M+H) + 347.1429. found 347.1516.

b) (+) and (−)-2-(methoxy(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(methoxy(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a CHIRALPAK® AS-H column with 20% IPA (0.1% DEA) in CO 2 to give (+)-2-(methoxy(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =2.9 min) and (−)-2-(methoxy(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =6.0 min).

(±)-tert-Butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-hydroxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-hydroxy-7-methyl-1H-indole-1-carboxylate

To a mixture of (±)-tert-butyl 5-(benzyloxy)-4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 5-(benzyloxy)-4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-7-methyl-1H-indole-1-carboxylate (Example 26-B) (910 mg, 1.39 mmol) in THF (14 mL) was added Pd/C (10%, 222 mg), degassed twice with nitrogen and vacuum, and then stirred under hydrogen atmosphere overnight. The reaction was filtered, and rinsed with EtOAc, The volatiles were removed in vacuo to provide the title compounds as a mixture. MS (ESI+) m/z 563.0 (M+H).

(±)-tert-Butyl 5-(2-amino-2-oxoethoxy)-4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 5-(2-amino-2-oxoethoxy)-4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-7-methyl-1H-indole-1-carboxylate

To a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-hydr oxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-hydroxy-7-methyl-1H-indole-1-carboxylate (43.2 mg, 0.313 mmol), was added 2-bromoacetamide (43.2 mg, 0.313 mmol) in CH 3 CN (2.9 mL) followed by Cs 2 CO 3 (114 mg, 0.35 mmol). The reaction was stirred at 70° C. for 4 hours. The solid was filtered, and washed with EtOAc. The organics were concentrated and purified with FCC eluting with heptane/EtOAc (1:0 to 0:1) to provide a mixture of title compounds. MS (ESI+) m/z 620.2 (M+H).

(±)-2-((4-(1-(5-Cyano-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-7-methyl-1H-indol-5-yl)oxy)acetamide

The title compound was synthesized from a mixture of (±)-tert-butyl 5-(2-amino-2-oxoethoxy)-4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 5-(2-amino-2-oxoethoxy)-4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-7-methyl-1H-indole-1-carboxylate as described in Example 24-B. 1 H NMR (TFA salt, 400 MHz, MeOH-d 4 ) δ ppm 8.04 (s, 1H) 7.63-7.85 (m, 2H) 7.31 (d, J=3.28 Hz, 1H) 7.01 (d, J=3.28 Hz, 1H) 6.69 (s, 1H) 4.37-4.49 (m, 1H) 4.24-4.35 (m, 1H) 2.49 (s, 3H) 2.31 (s, 3H). HRMS calcd. for C 21 H 19 N 5 O 3 (M+H) + 390.1561. found 390.1561.

(±)-tert-Butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-(2-methoxy-2-oxoethoxy)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-(2-methoxy-2-oxoethoxy)-7-methyl-1H-indole-1-carboxylate

The title compounds were synthesized from a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-hydroxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-hydroxy-7-methyl-1H-indole-1-carboxylate as described in Example 31-B using methyl 2-bromoacetate as electrophile in place to 2-bromoacetamide. MS (ESI+) m/z 635.4 (M+H).

(±)-2-((4-(1-(5-Cyano-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-7-methyl-1H-indol-5-yl)oxy)acetic acid

A mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-(2-methoxy-2-oxoethoxy)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-(2-methoxy-2-oxoethoxy)-7-methyl-1H-indole-1-carboxylate was fully deprotected using the same procedure as described in Example 24-B to give the title compound. 1 H NMR (TFA salt, 400 MHz, MeOH-d 4 ) δ ppm 8.06 (s, 1H) 7.79 (s, 2H) 7.31 (d, J=3.28 Hz, 1H) 6.92 (d, J=3.28 Hz, 1H) 6.70 (s, 1H) 4.49 (m, 2H) 2.50 (s, 3H) 2.30 (s, 3H). HRMS calcd. for C 21 H 18 N 4 O 4 (M+H) + 391.1401. found 391.1394.

(±)-tert-Butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

A mixture of tert-butyl 4-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and tert-butyl 4-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 25-A) (1.30 g, 2.32 mmol) in THF (23 mL) at 0° C. was added trifluoromethyltrimethylsilane (3.62 mL, 23.18 mmol), followed by TBAF (1M in THF) (23.18 mL, 23.18 mmol). The reaction mixture was warmed to room temperature and stirred for 15 min. At this point the reaction mixture was cooled to 0° C. and diluted with water. The layers were separated and the aqueous layer was extracted with EtOAc. The organics extracts were combined, dried over Na 2 SO 4 , filtered, concentrated and purified by flash chromatography (0-50% ethyl acetate in heptane) to provide the mixture of title compounds. MS (ESI+) m/z 631.43 (M+H).

a) (±)-2-(2,2,2-Trifluoro-1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

A mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (2.2 g, 3.49 mmol) was dissolved in 1.25 M HCl in MeOH (55.8 mL, 69.8 mmol) and heated at 60° C. for 17 hours. The reaction was cooled to room temperature and the solvent was removed in vacuo. The resulting residue was diluted with MeOH and basified by adding NH 4 OH. The crude mixture was directly loaded onto a silica column and purified by flash chromatography (0-100% ethyl acetate in heptanes) to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 with about 5 μL TFA) δ ppm 11.00 (br. s., 1H) 8.11 (s, 1H) 7.61-7.69 (m, 1H) 7.55-7.60 (m, 1H) 7.24 (t, J=2.84 Hz, 1H) 6.75 (s, 1H) 6.50 (br. s., 1H) 3.29 (s, 3H) 2.47 (d, J=0.51 Hz, 3H). HRMS calcd. for C 20 H 16 F 3 N 4 O 2 (M+H) + 401.122. found 401.1226.

b) (+) and (−)-2-(2,2,2-trifluoro-1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(2,2,2-trifluoro-1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a CHIRALPAK® AD-H column with 20% MeOH in CO 2 to give (−)-2-(2,2,2-trifluoro-1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =3.1 min) and (+)-2-(2,2,2-trifluoro-1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =4.8 min).

The following compounds were prepared with similar method.

(±)-tert-Butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-methoxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-methoxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

To a solution of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (100 mg, 0.159 mmol) in DMF (1.6 mL) was added successively MeI (0.3 mL, 4.8 mmol) and NaH (60%, 9.5 mg, 0.24 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min. At this point the reaction was quenched with 1.5 mL of a saturated aq. solution of NH 4 Cl and extracted with EtOAc. The layers were separated and the organic layer was washed with water. The combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated. The resulting residue was purified by flash chromatography (0-35% ethyl acetate in heptane) to provide the mixture of title compounds. MS (ESI+) m/z 645.44 (M+H).

a) (±)-2-(2,2,2-Trifluoro-1-methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-methoxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-methoxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate using the same procedure as described in Example 24-B. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.76-13.01 (m, 1H) 11.06 (br. s., 1H) 8.27 (s) 7.82-7.92 (m) 7.50-7.66 (m, 2H) 7.36 (t, J=2.78 Hz, 1H) 6.65-6.79 (m, 2H) 3.19 (s, 3H) 3.10 (s, 3H). HRMS calcd. for C 21 H 17 F 3 N 4 O 2 (M+H) + 415.1379. found 415.1376.

b) (+) and (−)-2-(2,2,2-trifluoro-1-methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(2,2,2-trifluoro-1-methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a CHIRALPAK® AD-H column with 20% MeOH in CO 2 to give (−)-2-(2,2,2-trifluoro-1-methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =5.8 min) and (+)-2-(2,2,2-trifluoro-1-methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =7.5 min).

(±)-tert-Butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(2-methoxy-2-oxoethoxy)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(2-methoxy-2-oxoethoxy)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

To a solution of a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 33-A) (500 mg, 0.79 mmol) in DMF (8 mL), NaH (60%, 95 mg, 2.38 mmol) was added at 0° C. After stirring for 10 minutes, methyl 2-bromoacetate (0.26 mL, 2.38 mmol) was added at the same temperature. The reaction mixture was warmed to room temperature and then stirred at 50° C. for 3 hours. The reaction was quenched with sat. aq. NH 4 Cl. The mixture was diluted with 80% EtOAc in heptanes. The layers were separated and the organic layer was washed with water. The organic extract was dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified with FCC eluting with heptane/EtOAc (0-40%) to provide the mixture of title compounds. MS (ESI+) m/z 703.1 (M+H).

a) (±)-Methyl 2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetate

A mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(2-methoxy-2-oxoethoxy)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(2-methoxy-2-oxoethoxy)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (510 mg, 0.711 mmol) was dissolved in 1.25 N HCl in MeOH (8.6 mL, 10.75 mmol), and stirred at 60° C. for 7 hours. The reaction mixture was then concentrated to dryness, dissolved in EtOAc, basified with a 15% aq. NH 4 OH solution at 0° C. and diluted with water. The organic layer was separated, dried over magnesium sulfate, filtered, concentrated and purified via FCC eluting with Heptane/EtOAc (0-60% of EtOAc) to provide the title compound. 1 H NMR (400 MHz, Acetone) δ ppm 11.86 (br. s., 1H) 10.15 (br. s., 1H) 7.54-8.07 (m) 7.48 (d, J=8.08 Hz, 1H) 7.25 (t, J=2.91 Hz, 1H) 6.91-7.05 (m, 1H) 6.64 (s, 1H) 4.31 (m, 1H) 3.92-4.05 (m, 1H) 3.30-3.45 (s, 3H) 2.97-3.13 (s, 3H) 2.35-2.46 (s, 3H) HRMS calcd. for C 23 H 19 F 3 N 4 O 4 (M+H) + 473.1437. found 473.1438.

b) (+) and (−)-Methyl 2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetate

Resolution of the enantiomers of methyl 2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetate was achieved by chiral SFC using a CHIRALPAK® IA column with 25% isopropanol in CO 2 to give (+) or (−)-methyl 2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetate (t r =2.4 min) and (−) or (+)-methyl 2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetate (t r =3.5 min).

(+) and (−)-2-(1-(5-Cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetic acid

(+) or (−)-Methyl 2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetate (t r =2.4 min—from Example 35-B) (116 mg, 0.246 mmol) was dissolved in THF (1.2 mL) and MeOH (1.2 mL). A 3N aq. NaOH solution (0.45 mL, 1.35 mmol) was added. The reaction was stirred at 40° C. for 1 hour. At this point the reaction mixture was concentrated. The residue was dissolved in MeOH, and purified with RP-HPLC(HC-A) to provide (−)-2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetic acid.

(−) or (+)-methyl 2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetate (t r =3.5 min—from Example 35-B) (110 mg, 0.233 mmol) was dissolved in THF (1.2 mL) and MeOH (1.2 mL). A 3N aq. NaOH solution (0.45 mL, 1.35 mmol) was added. The reaction was stirred at 40° C. for 1 hour. At this point the reaction mixture was concentrated. The residue was dissolved in MeOH, and purified with RP-HPLC(HC-A) to provide (+)-2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetic acid.

1 H NMR (TFA salt, 400 MHz, Acetone-d 6 ) δ ppm 10.13 (br. s., 1H) 7.95 (s, 1H) 7.65 (d, J=8.34 Hz, 1H) 7.48 (dd, J=8.34, 1.52 Hz, 1H) 7.24 (t, J=2.91 Hz, 1H) 7.03 (t, J=2.53 Hz, 1H) 6.64 (s, 1H) 4.29 (d, J=16.17 Hz, 1H) 3.97 (d, J=16.17 Hz, 1H) 3.06 (s, 3H) 2.41 (s, 3H). HRMS calcd. for C 22 H 17 F 3 N 4 O 4 (M+H) + 459.1275. found 459.1283.

(+) or (−)-Ethyl 2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetate

(+) or (−)-Methyl 2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetate (t r =3.5 min—from Example 35-B) (54 mg, 0.114 mmol) was dissolved in ethanol (2.0 mL). This solution was added to a mixture of acetyl chloride (1.0 mL) in ethanol (20.0 mL) at 0° C. This mixture was gradually warmed to room temperature and stirred for 16 hr. The reaction solution was basified with saturated sodium bicarbonate solution and the majority of the ethanol was removed in vacuo. The resulting reaction mixture was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. This material was purified using FCC eluting with ethyl acetate/heptane (0-60%) to afford the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.89 (br.s., 1H) 11.09 (br. s., 1H) 8.26 (s, 1H) 7.83-8.06 (m, 1H) 7.49-7.73 (m, 1H) 7.38 (t, J=2.78 Hz, 1H) 6.91-6.96 (m, 1H) 6.74 (s, 1H) 3.98-4.36 (m, 2H) 3.73-3.97 (m, 2H) 3.04-3.06 (s, 3H) 2.47-2.50 (s, 3H) 0.97-1.08 (m, 3H) HRMS calcd. for C 24 H 21 F 3 N 4 O 4 (M+H) + 487.1548. found 487.1576.

(±)-Tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(2-ethoxy-1-fluoro-2-oxoethoxy)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(2-ethoxy-1-fluoro-2-oxoethoxy)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

To a solution of a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 33-A) (100 mg, 0.159 mmol) in DMF (1 mL), NaH (60%, 19 mg, 0.476 mmol) was added at 0° C. After stirring for 10 minutes, ethyl-2-bromo-2-fluoroacetate (0.056 mL, 0.476 mmol) was added at the same temperature. The reaction mixture was warmed to room temperature and then stirred at 50° C. for 3 hours. The reaction was quenched with sat. aq. NH 4 Cl. The mixture was diluted with 80% EtOAc in heptanes. The layers were separated and the organic layer was washed with water. The organic extract was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified with FCC eluting with ethyl acetate/heptane (0-40%) to provide the mixture of title compounds. MS (ESI+) m/z 735.5 (M+H).

(±)-Ethyl 2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)-2-fluoroacetate

To a solution of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(2-ethoxy-1-fluoro-2-oxoethoxy)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(2-ethoxy-1-fluoro-2-oxoethoxy)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 35-E) (94 mg, 0.128 mmol) in dichloromethane (2.0 ml) at 0° C. was added SnCl 4 (1.0 M in DCM, 1.279 mL, 1.279 mmol); this mixture was stirred at 0° C. for 30 min followed by warming to room temperature and stirring for 1.0 hr additional. The reaction mixture was partitioned between EtOAc/saturated sodium bicarbonate solution upon which an emulsion formed. Both layers were filtered over a plug of Celite® and then returned to the separatory funnel as two distinct layers. The organic layer was washed with brine solution, dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified with FCC eluting with ethyl acetate/heptane (0-100%) to provide the title compound. MS (ESI+) m/z 505.2 (M+H).

(±)-2-(1-(5-Cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)-2-fluoroacetic acid

To a solution of (±)-ethyl 2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)-2-fluoroacetate (Example 35-F) (60 mg, 0.119 mmol) in THF (1.0 mL), water (1.0 mL) and MeOH (0.20 mL) was added LiOH (25 mg, 0.595 mmol) and this mixture was stirred for 16 hr at room temperature. The reaction was partitioned between EtOAc and cold 1N HCl solution and the layers separated and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. This material was purified with FCC eluting with dichloromethane/MeOH (0-10%) to afford the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.03 (br.s., 1H) 10.96 (br.s, 1H), 8.17-8.34 (br.s., 1H) 7.78-7.97 (br.s., 1H) 7.53-7.59 (m, 1H) 7.19-7.29 (m, 1H) 7.00-7.02 (br.s, 1H) 6.74-6.79 (br.s., 1H), 6.65 (s., 1H), 4.87-5.37 (m, 1H) 3.01 (s, 3H) 2.46 (s, 3H). HRMS calcd. for C 22 H 16 F 4 N 4 O 4 (M+H) + 477.1141. found 477.1154.

(±)-tert-Butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(2-ethoxy-2-oxoethoxy)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(2-methoxy-2-oxoethoxy)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

To a solution of a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 33-A) (506 mg, 0.80 mmol) in DMF (5 mL), NaH (60%, 96 mg, 2.41 mmol) was added at 0° C. After stirring for 10 minutes, ethyl 2-bromoacetate (0.267 mL, 2.41 mmol) was added at the same temperature. The reaction mixture was warmed to room temperature and then stirred at 50° C. for 3 hours. The reaction was quenched with sat. aq. NH 4 Cl. The mixture was diluted with 80% EtOAc in heptanes. The layers were separated and the organic layer was washed with water. The organic extract was dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified with FCC eluting with ethyl acetate/heptane (0-40%) to provide the mixture of title compounds. MS (ESI+) m/z 717.4 (M+H).

(±)-2-(1-(1-(tert-Butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)-1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethoxy)acetic acid and (±)-2-(1-(1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)-1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethoxy)acetic acid

To a solution of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(2-ethoxy-2-oxoethoxy)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(2-methoxy-2-oxoethoxy)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (528 mg, 0.737 mmol) in THF (3.0 mL), water (3.0 mL) and EtOH(0.25 mL) was added LiOH(155 mg, 3.68 mmol) and this mixture was stirred for 16 hr at room temperature. The reaction was partitioned between EtOAc and cold 1N HCl solution and the layers separated and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. This material was used without further purification to provide the mixture of title compounds. MS (ESI+) m/z 689.4 (M+H).

(±)-tert-butyl 4-(1-(2-(2-acetylhydrazinyl)-2-oxoethoxy)-1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(2-(2-acetylhydrazinyl)-2-oxoethoxy)-1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

To a solution of (±)-2-(1-(1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)-1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethoxy)acetic acid and (±)-2-(1-(1-(tert-butoxycarbonyl)-5-methoxy-7-methyl-1H-indol-4-yl)-1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethoxy)acetic acid (Example 35-I) (100 mg, 0.145 mmol) in DMF (1.0 mL) was added acetohydrazide (27 mg, 0.218 mmol), 1-hydroxy-7-azabenzotriazole (30 mg, 0.218 mmol), diisopropylethylamine (0.051 mL, 0.29 mmol) and N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide hydrochloride (42 mg, 0.218 mmol). This mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and cold 1N HCl solution and the layers were separated. The organic phase was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated in vacuo to afford the mixture of title compounds. The material was used as is for the next step without further purification. MS (ESI+) m/z 745.5 (M+H).

(±)-tert-Butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate compound and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

To a solution of (±)-tert-butyl 4-(1-(2-(2-acetylhydrazinyl)-2-oxoethoxy)-1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(2-(2-acetylhydrazinyl)-2-oxoethoxy)-1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 35-J) (108 mg, 0.145 mmol) in THF (2.0 mL) was added methyl N-(triethylammoniumsulfonyl)carbamate (70 mg, 0.290 mmol). This mixture was stirred and heated at 60° C. for 24 hours. The reaction mixture was concentrated down and purified directly by using FCC eluting with ethyl acetate/heptane (0-100%) to afford the mixture of title compound. MS (ESI+) m/z 727.4 (M+H).

(±)-2-(2,2,2-Trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)-1-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate compound and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 35-K) (38 mg, 0.051 mmol) in dichloromethane (1.0 mL) at 0° C. was added a 1.0M solution of SnCl 4 in dichloromethane (0.51 mL, 0.51 mmol). This mixture was stirred at 0° C. for 30 min and then warmed to room temperature and stirred for an additional 1.0 hr. The crude reaction mixture was diluted with ethyl acetate and a saturated sodium bicarbonate solution and the layers were passed over Celite® and then separated. The organic phase was washed with brine solution, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified using FCC eluting with ethyl acetate/heptane (0-100%) to afford the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 13.00 (br.s., 1H) 11.10 (br. s., 1H) 8.30 (s, 1H) 7.82-7.93 (m, 1H) 7.49-7.64 (m, 1H) 7.36 (t, J=2.91 Hz, 1H) 6.76 (s, 1H) 6.68 (br. s., 1H) 4.47-4.82 (m, 2H) 3.11 (s, 3H) 2.40 (s, 3H) 1.24 (s, 3H). HRMS calcd. for C 24 H 19 F 3 N 6 O 3 (M+H) + 497.1535. found 497.1504.

(±)-tert-Butyl 5-methoxy-7-methyl-4-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indole-1-carboxylate

To a solution of tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 19-D) (0.44 g, 1.52 mmol) in THF (7.24 mL), trimethyl(trifluoromethyl)silane (0.71 mL, 4.56 mmol) and then TBAF (1M in THF, 4.56 mL, 4.56 mmol) were added at 0° C., and the reaction was stirred at room temperature. After 20 minutes the reaction mixture was diluted with aq. NH 4 Cl and brine, extracted with EtOAc, and the organic extract was dried over MgSO 4 , filtered and concentrated. The resulting residue was purified by flash chromatography (0-70% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 360.1 (M+H).

tert-Butyl 5-methoxy-7-methyl-4-(2,2,2-trifluoroacetyl)-1H-indole-1-carboxylate

To a solution of (±)-tert-butyl 5-methoxy-7-methyl-4-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indole-1-carboxylate (0.46 g, 1.28 mmol) in DCM (13 mL), Dess-Martin periodinane (0.814 g, 1.920 mmol) was added, and the reaction was stirred at room temperature. After 10 minutes the reaction mixture was quenched with aq. NaHCO 3 and aq. sodium thiosulfate. The layers were separated and the aqueous layer was extracted with DCM. The combined organic extracts were dried over MgSO 4 , filtered and concentrated. The resulting residue was purified by flash chromatography (0-50% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 358.3 (M+H).

(±)-tert-Butyl 4-(1-((tert-butylsulfinyl)imino)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

To a solution of tert-butyl 5-methoxy-7-methyl-4-(2,2,2-trifluoroacetyl)-1H-indole-1-carboxylate (0.45 g, 1.26 mmol) and 2-methyl-2-propanesulfinamide (0.46 g, 3.78 mmol) in toluene (12.6 mL), Zr(O-t-Bu) 4 (2.52 mL, 6.30 mmol) was added at room temperature, and the reaction was heated to 100° C. After 15 minutes the reaction mixture was cooled to room temperature and diluted with EtOAc and sat. aq. brine. The resulting mixture was filtered and the layers separated. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried over MgSO 4 , filtered and concentrated. The resulting residue was purified by flash chromatography (0-50% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 461.3 (M+H).

(±)-tert-Butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

To a solution of a mixture of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (0.62 g, 2.26 mmol) in THF (10 mL), LDA in heptane/THF/ethylbenzene (1.8M, 1.13 mL, 2.03 mmol) was added at −78° C. After stirring for 30 min., a solution of (±)-tert-butyl 4-(1-((tert-butylsulfinyl)imino)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (0.52 g, 1.129 mmol) in THF (5 mL) was added to the reaction mixture. After stirring for 10 minutes the reaction mixture was warmed to 0° C., stirred for 2 minutes, then successively diluted with MeOH (2 mL), sat. aq. NH 4 Cl (10 mL), sat. aq. brine (10 mL) and EtOAc (30 mL). The layers were separated and the aqueous layer was extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO 4 , filtered, and concentrated. The resulting residue was purified by flash column chromatography (0-100% EtOAc in heptanes) to provide a mixture of the title compounds. MS (ESI+) m/z 734.4 (M+H).

a) (±)-2-(1-Amino-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

A mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (0.50 g, 0.68 mmol) was dissolved in 1.25M HCl in MeOH (10.9 mL, 13.63 mmol) and the mixture was heated at 60° C. After 4 hours the reaction was cooled to room temperature and concentrated. The residue was dissolved in MeOH (6.81 mL) and Cs 2 CO 3 (2.22 g, 6.81 mmol) was added, and the mixture was stirred at 60° C. After 30 minutes additional Cs 2 CO 3 (1.11 g, 3.4 mmol) was added. After 10 minutes the reaction was diluted with sat. aq. NH 4 Cl and the layers separated. The aqueous layer was extracted with EtOAc, dried over MgSO 4 , filtered and concentrated. The resulting residues was purified by flash column chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 with about 5 μL TFA) δ ppm 11.19 (br. s., 1H) 8.27 (br. s., 1H) 7.78 (d, J=7.96 Hz, 1H) 7.69 (dd, J=8.46, 1.52 Hz, 1H) 7.13 (t, J=2.91 Hz, 1H) 6.94 (s, 1H) 5.09 (br. s., 1H) 3.77 (s, 3H). HRMS calcd. for C 20 H 16 F 3 N 6 O (M+H) + 400.138. found 400.1385.

b) (+) and (−)-2-(1-amino-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(1-amino-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a CHIRALPAK® AD-H column with 20% MeOH in CO 2 to give (−)-2-(1-amino-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =3.6 min) (MP=255° C., when crystallized from a 1.5:1 mixture of EtOH:H 2 O) and (+)-2-(1-amino-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =6.2 min).

(+)-2-(6-methoxy-8-methyl-5-(trifluoromethyl)-1,3,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-5-yl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was isolated from the reaction mixture leading to Example 36-E b) (−), which was synthesized as described in Example 36-A to 36-E using (R)-(+)-2-methyl-2-propanesulfinamide in Example 36-C, as a minor product (<1% yield) using SFC with a Whelk-O (R,R) column (25% IPA in CO 2 ) followed by flash chromatography (0-60% EtOAc:DCM). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.36-12.51 (m, 1H) 10.84 (s, 1H) 8.15-8.28 (m) 7.84 (m) 7.75 (m) 7.54 (dd, J=8.21, 1.39 Hz, 1H) 7.47 (m) 7.14 (s, 1H) 6.68 (s, 1H) 4.07-4.29 (m, 2H) 3.72-3.82 (m, 1H) 3.22 (s, 3H) 2.47 (s, 3H). HRMS calcd for C 21 H 16 F 3 N 6 O (M+H) + 412.1385. found 412.1382.

(±)-2-(1-Amino-2,2,2-trifluoro-1-(5-isopropoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized as described in Example 36-A to 36-E starting from tert-butyl 4-formyl-5-isopropoxy-7-methyl-1H-indole-1-carboxylate (Example 19-G). 1 H NMR (TFA salt, 400 MHz, CD 3 OD) δ ppm 8.03 (br.s, 1H) 7.70 (d, J=8.34 Hz, 1H) 7.64 (d, J=8.34 Hz, 1H) 7.25 (app d, J=2.78 Hz, 1H) 6.81 (s, 1H) 6.32 (br.s, 1H) 4.65-4.58 (m, 1H) 2.53 (s, 3H) 0.96 (d, J=5.94 Hz, 3H) 0.82 (d, J=5.94 Hz, 3H). HRMS calcd. for C 22 H 20 F 3 N 6 O (M+H) + 428.1687. found 428.1696.

(±)-tert-Butyl 4-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(methylamino)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-1-(dimethylamino)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

To a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 33-A) (1.27 g, 2.014 mmol) was added 1.25 M HCl in MeOH (16.11 mL, 20.14 mmol) and the mixture was stirred at 60° C. After 40 minutes the reaction was cooled to room temperature and concentrated. The mixture was dissolved in CHCl 3 (40 mL), then was added thionyl chloride (1.47 mL, 20.14 mmol) and DMF (0.5 mL) and the mixture was heated at 70° C. After 10 minutes the reaction was cooled to room temperature and concentrated. At this point the reaction was dissolved in 33% methylamine in EtOH (25 mL, 201 mmol) and stirred at room temperature. After 5 minutes the mixture was concentrated and the resulting residue was purified directly by flash chromatography (0-100% EtOAc in heptanes) to provide (±)-tert-butyl 4-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(methylamino)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate. MS (ESI+) m/z 514.3 (M+H). In addition, (±)-tert-butyl 4-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-1-(dimethylamino)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate was also isolated. MS (ESI−) m/z 526.3 (M−H).

a) (±)-2-(2,2,2-Trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of (±)-tert-butyl 4-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(methylamino)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (0.87 g, 1.69 mmol) in MeOH (16.94 mL) at room temperature, Cs 2 CO 3 (2.76 g, 8.47 mmol) was added and the reaction was stirred at 60° C. After 2.5 hours the reaction was cooled to room temperature, quenched with aq. NH 4 Cl. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over MgSO 4 , filtered and concentrated. The resulting residue was purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 with about 5 μL TFA) δ ppm 11.14 (br. s., 1H) 8.21 (br. s., 1H) 7.72 (d, J=8.46 Hz, 1H) 7.64 (dd, J=8.40, 1.45 Hz, 1H) 7.18 (t, J=2.84 Hz, 1H) 6.89 (s, 1H) 5.56 (br. s., 1H) 3.57 (br. s., 3H) 2.31 (s, 3H). HRMS calcd. for C 21 H 18 F 3 N 5 O (M+H) + 414.1542. found 414.1542.

b) (+) and (−)-2-(2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a CHIRALCEL® OD-H column with 20% MeOH (0.2% DEA) in CO 2 to give (+)-2-(2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =2.7 min) and (−)-2-(2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =4.1 min).

(±)-2-(1-(Dimethylamino)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compounds was synthesized starting from tert-butyl 4-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-1-(dimethylamino)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate following a similar method as in Example 38-B. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.20-12.40 (m, 1H) 10.97 (br. s., 1H) 8.22 (m) 7.80-7.91 (m) 7.50-7.64 (m) 7.33 (br. s., 1H) 7.02 (br. s., 1H) 6.72 (s, 1H) 3.07 (s, 3H) 2.48 (br. s., 3H) 2.28 (s, 6H). HRMS calcd. for C 22 H 20 F 3 N 5 O (M+H) + 428.1698. found 428.1695.

a) (±)-2-(1-((2-aminoethyl)amino)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized as shown in the sequence in Example 38-A and B. Ethylenediamine was used in place of methylamine in Example 38-A. 1 H NMR (400 MHz, DMSO-d 6 with about 5 μL TFA) δ ppm 11.04 (br. s., 1H) 8.16 (br. s., 1H) 7.67 (br. s., 1H) 7.60 (dd, J=8.34, 1.52 Hz, 1H) 7.49 (br. s., 1H) 7.14 (br. s., 1H) 6.84 (s, 1H) 3.52 (br. s., 3H) 2.72-2.95 (m, 3H) 2.47 (s, 3H) 2.14-2.31 (m, 1H). HRMS calcd. for C 22 H 21 F 3 N 6 O (M+H) + 443.1807. found 443.1793.

b) (+) and (−)-2-(1-((2-aminoethyl)amino)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(1-((2-aminoethyl)amino)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a CHIRALPAK® IA column with 30% IPA+5% isopropylamine in CO 2 to give (−)-2-(1-((2-aminoethyl)amino)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =2.9 min) and (+)-2-(1-((2-aminoethyl)amino)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =3.5 min).

(±)-tert-Butyl 4-(((tert-butylsulfinyl)imino)(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(((tert-butylsulfinyl)imino)(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

A mixture of tert-Butyl 4-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and tert-butyl 4-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (1 g, 1.78 mmol), 2-methylpropanesulfinamide (0.24 g, 1.96 mmol) and Ti(O-i-Pr) 4 (3.66 mL, 12.48 mmol) was stirred at 90° C. for 5 hours. The reaction was cooled to room temperature and diluted with EtOAc and brine. The resulting mixture was filtered and the layers were separated. The organic layer of the filtrate was dried over sodium sulfate, filtered, concentrated and purified by flash chromatography (0-50% EtOAc in heptanes) to provide the mixture of title compounds. MS (ESI+) m/z 664.6 (M+H).

(±)-tert-Butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(1,1-dimethylethylsulfinamido)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(1,1-dimethylethylsulfinamido)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

To a mixture of (±)-tert-butyl 4-(((tert-butylsulfinyl)imino)(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(((tert-butylsulfinyl)imino)(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (53 mg, 0.095 mmol) in MeOH (3 mL) was added NaBH 4 (71.5 mg, 1.89 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM and water and filtered. The filtrate was washed with H 2 O and brine, passed through a phase separator, concentrated and purified by flash chromatography (0-5% MeOH in DCM) to provide the mixture of title compounds. MS (ESI+) m/z 666.6 (M+H).

a) (±)-2-(Amino(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from a mixture of (±)-tert-butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(1,1-dimethylethylsulfinamido)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(1,1-dimethylethylsulfinamido)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate following the same procedure as described in Example 36-E. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.91 (br. s., 1H) 7.91 (s, 1H) 7.57 (d, J=8.08 Hz, 1H) 7.47 (dd, J=8.34, 1.52 Hz, 1H) 7.19 (t, J=2.78 Hz, 1H) 6.74 (s, 1H) 6.23 (dd, J=3.03, 2.02 Hz, 1H) 5.80 (s, 1H) 3.71 (s, 3H) 2.44 (s, 3H). HRMS calcd. for C 19 H 17 N 5 O (M+H) + 332.1506. found 332.1507.

b) (+) and (−)-2-(amino(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(amino(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile is achieved by chiral HPLC using a CHIRALPAK® AD-H column with 10% ethanol (0.2% DEA) in heptanes to give (−) or (+)-2-(amino(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =24.09 min) and (+) or (−)-2-(amino(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile=30.56 min)

(±)-2-(Amino(5-isopropoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized as described in Example 39 starting from tert-butyl 4-formyl-5-isopropoxy-7-methyl-1H-indole-1-carboxylate. 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.85 (br.s, 1H) 7.58 (d, J=8.38 Hz, 1H) 7.48 (app dd, J=8.38, 1.45 Hz, 1H) 7.20 (d, J=3.16 Hz, 1H), 6.75 (s, 1H) 6.34 (d, J=3.16 Hz, 1H) 5.80 (s, 1H) 4.57-4.48 (m, 1H) 2.48 (s, 3H) 1.22 (d, J=6.06 Hz, 3H) 0.83 (d, J=6.06 Hz, 3H). HRMS calcd. for C 22 H 21 N 5 O (M+H) + 360.1819. found 360.1811.

(±)-tert-Butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

To a solution of a mixture of (±)-tert-butyl 4-(((tert-butylsulfinyl)imino)(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(((tert-butylsulfinyl)imino)(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 39-A) (0.46 g, 0.69 mmol) in THF (6.93 mL), MeMgCl (3M in THF) (0.69 mL, 2.08 mmol) was added at 0° C. and stirred for 30 minutes. The reaction was quenched with aq. NH 4 Cl and diluted with EtOAc. The layers were separated and the organic layer was removed, dried with sodium sulfate, filtered, concentrated and purified by flash chromatography (0-100% EtOAc in heptanes) to provide the mixture of title compounds. MS (ESI+) m/z 680.6 (M+H).

a) (±)-2-(1-Amino-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

To a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (0.52 g, 0.76 mmol) was added 1.25 M HCl in MeOH (6.12 mL, 7.65 mmol) and heated at 60° C. for 30 minutes. The reaction was concentrated and then diluted with MeOH (5 mL). Cs 2 CO 3 (4 g, 12.28 mmol) was added and the reaction was heated at 60° C. After 2 hours the reaction was complete. Reaction was then cooled and quenched with 10 mL of a saturated aq. solution of ammonium chloride and diluted with 50 mL of ethyl acetate. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics layers were dried over magnesium sulfate, concentrated and purified by flash chromatography [0-10% (10% ammonium hydroxide in MeOH)-DCM] to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 with ˜5 μL TFA) δ ppm 11.23 (br. s., 1H) 8.82 (br. s., 3H) 7.47-7.76 (m, 1H) 7.35 (t, J=2.97 Hz, 1H) 6.87 (s, 1H) 5.94 (dd, J=3.16, 1.77 Hz, 1H) 3.50 (s, 3H) 2.04-2.37 (m, 3H). HRMS calcd. for C 20 H 13 N 6 O (M+H) + 346.1663. found 346.1663.

b) (+) and (−)-2-(1-amino-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(1-amino-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a CHIRALPAK® AD-H column with 15% MeOH in CO 2 to give (−)-2-(1-amino-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =4.2 min) (MP=201° C., when crystallized from a 3:1 mixture of MeOH:H 2 O), and (+)-2-(1-amino-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =7.1 min).

(±)-tert-Butyl 4-(1-amino-1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-amino-1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

To a solution of a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (0.54 g, 0.79 mmol) in anhydrous MeOH (1.6 mL) was added 1.25 M HCl in MeOH (3.18 mL, 3.97 mmol) and stirred at room temperature for 5 hours. The reaction was diluted with MeOH and 2M aq. Na 2 CO 3 (6 mL). The mixture was concentrated to remove the MeOH and then aqueous layer was extracted with EtOAc. The organic extract was dried over Na 2 SO 4 , filtered, concentrated and purified by flash column chromatography (0-10% MeOH in DCM) to provide the mixture of title compounds. MS (ESI+) m/z 576.5 (M+H).

(±)-tert-Butyl 4-(1-((tert-butoxycarbonyl)amino)-1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-((tert-butoxycarbonyl)amino)-1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

A mixture of (±)-tert-butyl 4-(1-amino-1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-5-methoxy-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-amino-1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (0.29 g, 0.504 mmol) and Boc 2 O (1.099 g, 5.04 mmol) was allowed to stir at 60° C. for 14 hours. The reaction was cooled to room temperature and purified by flash column chromatography on silica gel (0-50% EtOAc in heptanes) to obtain the title compounds as a mixture. MS (ESI+) m/z 676.5 (M+H).

(±)-tert-Butyl 4-(1-((tert-butoxycarbonyl)(methyl)amino)-1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-((tert-butoxycarbonyl)(methyl)amino)-1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

To a mixture of (±)-tert-butyl 4-(1-((tert-butoxycarbonyl)amino)-1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-((tert-butoxycarbonyl)amino)-1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (0.3 g, 0.44 mmol) in DMF (4.5 mL), NaH (60%, 0.053 g, 1.33 mmol) and then MeI (0.083 mL, 1.33 mmol) were added at 0° C. and the reaction was then stirred at room temperature. After 30 minutes the reaction was cooled in an ice bath and quenched with 5 mL of saturated aq. ammonium chloride and then diluted with EtOAc. The layers were separated and the organic layer was dried over magnesium sulfate, concentrated and purified by flash chromatography (0-50% EtOAc in heptanes) to provide the mixture of title compounds. MS (ESI+) m/z 690.5 (M+H).

a) (±)-2-(1-(5-Methoxy-7-methyl-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

A mixture of (±)-tert-butyl 4-(1-((tert-butoxycarbonyl)(methyl)amino)-1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-((tert-butoxycarbonyl)(methyl)amino)-1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (0.21 g, 0.304 mmol) was dissolved in anhydrous MeOH (0.61 mL) and cooled to 0° C. A 4 M HCl solution in dioxane (1.52 mL, 6.09 mmol) was added and the reaction was stirred in the ice bath for 5 hours. Anhydrous MeOH (0.6 mL) was added to the reaction followed by cesium carbonate (2.98 g, 9.13 mmol). The mixture was heated at 60° C. for 1 hour. At this point the reaction was concentrated and diluted with a saturated solution of aq. ammonium chloride and ethyl acetate. The layers were separated and the organic phase was dried over magnesium sulfate, concentrated and purified by flash chromatography [0-5% MeOH (containing 10% ammonium hydroxide) in DCM] to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.87 (br. s., 1H) 7.93 (m) 7.56 (m) 7.43-7.50 (m, 1H) 7.22 (br. s., 1H) 6.69 (s, 1H) 6.57 (br. s., 1H) 3.22 (s, 3H) 2.44 (s, 3H) 2.06 (s, 3H) 1.91 (s, 3H). HRMS calcd. for C 21 H 21 N 5 O (M+H) 360.1824. found 360.1831.

b) (+) and (−)-2-(1-(5-methoxy-7-methyl-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(1-(5-methoxy-7-methyl-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral HPLC using a CHIRALPAK® AD-H column with 15% Ethanol (0.05% DEA) in heptanes to give (−)-2-(1-(5-methoxy-7-methyl-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile=6.96 min) and (+)-2-(1-(5-methoxy-7-methyl-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =9.23 min).

(±)-tert-Butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(methylimino)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(methylimino)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

A mixture of tert-butyl 4-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and tert-butyl 4-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 25-A) (0.22 g, 0.39 mmol) was dissolved in a 2 M methyl amine in THF solution (3.98 mL, 7.96 mmol). Titanium(IV) isopropoxide (0.350 mL, 1.194 mmol) was added at 0° C. The reaction was then removed from the ice bath and left stirring for 15 minutes. The reaction was cooled in an ice bath and quenched with brine and then diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over magnesium sulfate and concentrated. The resulting residue was purified by flash column chromatography (0-30% EtOAc in heptanes) to provide the mixture of title compounds. (ESI+) m/z 574.4 (M+H).

(±)-tert-Butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(dimethylamino)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(dimethylamino)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate

A mixture of (±)-tert-butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methylimino)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(methylimino)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (50 mg, 0.044 mmol) was dissolved in THF (0.44 mL) and cooled to 0° C. Methyl magnesium chloride (3 M, 0.1 mL, 0.30 mmol) was added dropwise to the yellow solution and stirred for 30 minutes. The reaction was quenched with saturated aq. ammonium chloride. The layers were separated and the aqueous layer was then extracted with EtOAc. The organic phases were combined, dried over magnesium sulfate and concentrated to obtain the mixture of title compounds. MS (ESI+) m/z 590.6 (M+H).

(±)-2-((Dimethylamino)(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from a mixture of (±)-tert-butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(dimethylamino)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(dimethylamino)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate as described in Example 36-E. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.60 (s, 1H) 10.88 (s, 1H) 7.90 (s) 7.54-7.60 (m) 7.46 (m) 7.22 (t, J=2.78 Hz, 1H) 6.74 (s, 1H) 6.69 (dd, J=2.97, 1.96 Hz, 1H) 5.38 (s, 1H) 3.79 (s, 3H) 2.41 (d, J=0.63 Hz, 3H) 2.22 (s, 6H). MS (ESI−) m/z 358.2 (M−H).

tert-Butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)vinyl)-5-ethoxy-7-methyl-1H-indole-1-carboxylate and tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)vinyl)-5-ethoxy-7-methyl-1H-indole-1-carboxylate

To a solution of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-ethoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-ethoxy-7-methyl-1H-indole-1-carboxylate [synthesized as in Example 24-B, 25-A and 26-A starting from tert-butyl 5-ethoxy-4-formyl-7-methyl-1H-indole-1-carboxylate (Example 19-F)] (0.37 g, 0.65 mmol) in DCM (6.48 mL) was added DMAP (7.92 mg, 0.065 mmol) and TEA (4.52 mL, 32.4 mmol). At this point the reaction was cooled to 0° C. and MsCl (2.021 mL, 25.9 mmol) was added and the reaction stirred in an ice bath for 10 minutes. The reaction was then diluted with water and EtOAc. The layers were separated and the organic extract was dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by flash column chromatography (0-100% EtOAc in heptanes) to provide a mixture of title compounds. (ESI+) m/z 573.5 (M+H).

(±)-tert-Butyl 4-(2-amino-1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-5-ethoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(2-amino-1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-5-ethoxy-7-methyl-1H-indole-1-carboxylate

To a mixture of tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)vinyl)-5-ethoxy-7-methyl-1H-indole-1-carboxylate and tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)vinyl)-5-ethoxy-7-methyl-1H-indole-1-carboxylate (0.28 g, 0.489 mmol) was added 7 N ammonia in MeOH (4.89 mmol) and heated in a sealed tube at 80° C. for 15 hours. The reaction was concentrated to provide a mixture of title compounds. (ESI+) m/z 590.6 (M+H).

(±)-2-(2-amino-1-(5-ethoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was obtained from a mixture of (±)-tert-butyl 4-(2-amino-1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-5-ethoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(2-amino-1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)ethyl)-5-ethoxy-7-methyl-1H-indole-1-carboxylate as described in Example 24-B. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.87 (br. s., 1H) 7.96 (s, 1H) 7.53-7.61 (m, 1H) 7.44-7.52 (m, 1H) 7.12 (t, J=2.65 Hz, 1H) 6.76 (s, 1H) 5.98 (br. s., 1H) 5.34 (br. s., 2H) 4.86 (dd, J=8.08, 5.56 Hz, 1H) 3.98-4.08 (m, 1H) 3.89 (dd, J=9.35, 7.07 Hz, 1H) 3.66 (dd, J=12.63, 8.08 Hz, 1H) 3.03 (dd, J=12.63, 5.56 Hz, 1H) 2.43 (s, 3H) 1.16 (t, J=6.95 Hz, 3H). HRMS calcd. for C 21 H 21 N 5 O (M+H) 360.1824. found 360.1823.

(±)-2-(1-(5-ethoxy-7-methyl-1H-indol-4-yl)-2-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized as described in Example 44, methylamine (2 M in THF) was used instead of ammonia in Example 44-B. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.08 (br. s., 1H) 8.02 (br. s., 1H) 7.46-7.65 (m) 7.24 (t, J=2.78 Hz, 1H) 6.82 (s, 1H) 6.01 (br. s., 1H) 5.25 (dd, J=8.72, 5.43 Hz, 1H) 3.94-4.15 (m, 2H) 3.87 (dd, J=9.22, 7.20 Hz, 1H) 3.25-3.31 (m, 1H) 2.68 (s, 3H) 2.47 (s, 3H) 0.98-1.16 (m, 3H). HRMS calcd. for C 22 H 23 N 5 O (M+H) + 374.1976. found 374.1978.

5,7-Dimethyl-4-nitro-1-tosyl-1H-indole

To a solution of 5,7-dimethyl-4-nitro-1H-indole (CAS; 1190314-35-2, 10 g, 52.6 mmol) in DMF (200 mL) was added portionwise NaH (3.2 g, 60% in mineral oil, 79 mmol) at 0° C., and then the mixture was stirred at room temperature for 0.5 h. The mixture was cooled down to 0° C. To the red suspension was added TsCl (15.0 g, 79 mmol) at 0° C., and then the mixture was stirred at room temperature for 22 h. At this point, the reaction was quenched with half saturated aq. KHSO 4 solution. The mixture was diluted with H 2 O, and then the whole mixture was stirred at room temperature for 1 h. The resulted solid was collected by filtration. The obtained brown solid was successively washed with H 2 O, MeOH, and heptane. The solid was dried to give the title compound. MS (ESI+) m/z 345.1 (M+H).

5,7-Dimethyl-1-tosyl-1H-indol-4-amine

To a solution of 5,7-dimethyl-4-nitro-1-tosyl-1H-indole (17 g, 49.4 mmol) in MeOH (50 mL)/EtOAc (300 mL) was added Zn (16.1 g, 247 mmol). The suspension was cooled down to 0° C. To the suspension was added dropwise AcOH (30 mL) over 30 min, and then the mixture was stirred at 0° C. for 0.5 h. The flask was removed from the ice bath, and the mixture left stirring at room temperature for 18.5 h. The reaction mixture was poured into a mixture of Celite®/5% aq. NaHCO 3 /EtOAc, and then the basic mixture was vigorously stirred for 0.5 h. The mixture was filtered through Celite®. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic phase was washed with 5% aq. NaHCO 3 , H 2 O, and brine, dried over Na 2 SO 4 , and then filtered. Concentration of the filtrate gave the title compound, without need of further purification. MS (ESI+) m/z 315.1 (M+H).

4-Iodo-5,7-dimethyl-1-tosyl-1H-indole

To a suspension of 5,7-dimethyl-1-tosyl-1H-indol-4-amine (7.70 g, 24.5 mmol) in H 2 O (80 mL)/EtOAc (150 mL) was added conc. aq. HCl (4.3 mL, 49.0 mmol) at 0° C., and then the mixture was stirred at 0° C. To the suspension was added dropwise a solution of NaNO 2 (2.0 g, 29.4 mmol) in H 2 O (20 mL) over 15 min while keeping the temperature below 5° C. Once the addition was complete, the mixture was stirred at 0° C. for 1 h. To the mixture was added dropwise a solution of KI (12.2 g, 73.5 mmol) in H 2 O (20 mL) over 15 min, and then the mixture was stirred at 0° C. for 1 hr. The reaction was quenched by half saturated aqueous Na 2 S 2 O 3 solution, and then the whole mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, and then the layers were partitioned. The organic layer was washed with H 2 O and brine, dried over Na 2 SO 4 , and then filtered and concentrated. The resulting residue was purified by FCC [heptane/(30% EtOAc in CH 2 Cl 2 )=91/9 to 85/15)]. The resulting residue was triturated with Et 2 O, and then the solid was collected by filtration to give the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.92 (d, J=3.80 Hz, 1H), 7.61 (d, J=8.60 Hz, 2H), 7.40 (dd, J=0.50, 8.60 Hz, 2H), 7.04 (s, 1H), 6.72 (d, J=3.79 Hz, 1H), 2.41 (s, 3H), 2.37 (s, 3H), 2.34 (s, 3H).

5,7-Dimethyl-1-tosyl-1H-indole-4-carbaldehyde

To a solution of 4-iodo-5,7-dimethyl-1-tosyl-1H-indole (950 mg, 2.1 mmol) and DMF (0.33 mL, 4.2 mmol) in cyclopentyl methyl ether (22 mL), n-butyllithium in hexane (2.2 M, 1.3 mL, 2.8 mmol) was added at −78° C. After stirring for 1 h, additional n-butyllithium in hexane (2.2 M, 0.19 mL, 0.42 mmol) was added. After stirring for 15 min, the reaction was quenched with MeOH (2 mL) and 1M aq. NaHSO 4 (4.5 mL), and diluted with EtOAc and brine. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na 2 SO 4 , and then filtered. Concentration of the filtrate gave a residue that was purified by FCC [(10% DCM/heptane)/(20% EtOAc/DCM)=100/0 to 50/50] to give the title compound. MS (ESI+) m/z 328.2 (M+H).

(2-Chloro-4-methyl-5-nitrophenyl)methanol

To a solution of 2-chloro-4-methyl-5-nitrobenzoic acid (CAS; 101580-96-5, 15 g, 69.6 mmol) and triethylamine (11.1 mL, 80 mmol) in THF (200 mL) was added 1,1,1-trichloro-2-methylpropan-2-yl carbonochloridate (19.2 g, 80 mmol) at 0° C., and then the mixture was stirred at 0° C. for 1 hr. The resulting white solid was filtered off through Celite®. The solid was washed by THF (20 mL). To the filtrate was added NaBH 4 (3.2 g, 83 mmol) at 0° C., followed by H 2 O (50 mL). The mixture was stirred at 0° C. for 0.5 h, and then stirred at room temperature for 1.25 h. The reaction was quenched by half satd. KHSO 4 . The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 . The organic layers were combined, washed with H 2 O and brine, dried over Na 2 SO 4 , and then filtered through a silica pad. The SiO 2 cake was washed with EtOAc. The residue was concentrated and then triturated with heptane. The resulting solid was collected by filtration to give the title compound. 1 H NMR (400 MHz, ACETONITRILE-d 3 ) δ 8.11 (s, 1H), 7.47 (s, 1H), 4.68 (s, 2H), 2.53 (s, 3H).

(±)-2-((2-Chloro-4-methyl-5-nitrobenzyl)oxy)tetrahydro-2H-pyran

To a solution of (2-chloro-4-methyl-5-nitrophenyl)methanol (23 g, 114 mmol) and 3,4-dihydro-2H-pyran (20.9 mL, 228 mmol) in CH 2 Cl 2 (500 mL) was added pyridinium p-toluenesulfonate (5.7 g, 22.8 mmol), and then the mixture was stirred at room temperature for 11 h. The reaction was quenched by 5% aq. NaHCO 3 . The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 . The organic layers were combined and washed with H 2 O and brine, dried over Na 2 SO 4 , filtered and concentrated. The resulting residue was purified by SiO 2 column chromatography (heptane/EtOAc=96/4, isocratic) to give the title compound. 1 H NMR (400 MHz, ACETONITRILE-d 3 ) δ 8.10 (s, 1H), 7.49 (s, 1H), 4.81 (d, J=13.64 Hz, 1H), 4.72-4.78 (m, 1H), 4.59 (d, J=13.64 Hz, 1H), 3.77-3.92 (m, 1H), 3.34-3.60 (m, 1H), 2.54 (s, 3H), 1.68-1.91 (m, 2H), 1.43-1.68 (m, 4H).

(±)-5-Chloro-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-indole

To a suspension of vinylmagnesium bromide (1M in THF, 200 mL, 200 mmol) was added dropwise (±)-2-((2-chloro-4-methyl-5-nitrobenzyl)oxy)tetrahydro-2H-pyran (14 g, 49.0 mmol) in THF (40 mL) below −20° C. After completion of the addition, the flask was removed from the ice bath with stirring. After 2 h, the reaction mixture was cooled to below −20° C. The reaction was quenched with MeOH with maintaining the temperature below 0° C. The mixture was diluted with CH 2 Cl 2 and H 2 O. The mixture was filtered through Celite®. The Celite® cake was washed with CH 2 Cl 2 . The layers were separated and the organic phase was washed with H 2 O and brine, dried over Na 2 SO 4 , and then filtered. Concentration of the filtrate gave the title compound, which was used in the next reaction without any further purification. For an analytical purpose, the crude was purified by SiO 2 column chromatography [heptane/(30% EtOAc in CH 2 Cl 2 )]=69/31] to afford the title compound. 1 H NMR (400 MHz, ACETONITRILE-d 3 ) δ 9.43 (br. s., 1H), 7.29-7.36 (m, 1H), 6.99 (s, 1H), 6.58-6.70 (m, 1H), 5.05 (d, J=11.12 Hz, 1H), 4.84 (d, J=11.10 Hz, 1H), 4.67-4.77 (m, 1H), 3.89-4.03 (m, 1H), 3.46-3.60 (m, 1H), 2.47 (s, 3H), 1.59-1.75 (m, 2H), 1.43-1.59 (m, 4H)

(±)-5-Chloro-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole

To a solution of (±)-5-chloro-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-indole (8.95 g, 32 mmol) in CH 2 Cl 2 (150 mL), at 0° C. was added NaOH (2.56 g, 64.0 mmol), followed by triethylbenzylammonium chloride (0.729 g, 3.20 mmol) and TsCl (12.20 g, 64.0 mmol). The mixture was then stirred at room temperature. After 17 h, additional NaOH (1.28 g, 32.0 mmol), and TsCl (6.10 g, 32.0 mmol) were added. The mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with H 2 O, and was vigorously stirred for 1 h. The mixture was diluted with CH 2 Cl 2 and the organic layer was successively washed with H 2 O and brine, dried over Na 2 SO 4 , and then filtered. Concentration of the filtrate gave the crude product, which was purified by FCC [heptane/(30% EtOAc in CH 2 Cl 2 )=82/18 then 79/21] to give the title compound. 1 H NMR (400 MHz, ACETONITRILE-d 3 ) δ 7.84 (d, J=3.79 Hz, 1H), 7.67 (d, J=8.20 Hz, 1H), 7.59 (d, J=8.59 Hz, 1H), 7.48 (d, J=8.20 Hz, 1H), 7.33 (d, J=8.50 Hz, 1H), 7.13 (s, 1H), 6.97 (d, J=3.79 Hz, 1H), 4.97 (d, J=11.37 Hz, 1H), 4.76 (d, J=11.37 Hz, 1H), 4.61-4.70 (m, 1H), 3.79-3.91 (m, 1H), 3.40-3.52 (m, 1H), 2.53 (s, 3H), 2.36 (s, 3H), 1.58-1.75 (m, 2H), 1.38-1.58 (m, 4H).

(5-Chloro-7-methyl-1-tosyl-1H-indol-4-yl)methanol

A solution of (±)-5-chloro-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole (4.1 g, 9.5 mmol) and TsOH.H 2 O (359 mg, 1.9 mmol) in EtOH (50 mL) was stirred at room temperature for 21 h. The reaction mixture was concentrated. The mixture was diluted with CH 2 Cl 2 . The organic phase was successively washed with 5% aq. NaHCO 3 , H 2 O and brine, dried over Na 2 SO 4 , and then filtered. Concentration of the filtrate gave the title compound, without need of further purification. 1 H NMR (400 MHz, ACETONITRILE-d 3 ) δ 7.84 (d, J=3.79 Hz, 1H), 7.59 (d, J=8.34 Hz, 2H), 7.33 (d, J=8.34 Hz, 2H), 7.10 (s, 1H), 7.00 (d, J=3.79 Hz, 1H), 4.84 (d, J=5.81 Hz, 2H), 3.14 (t, J=5.81 Hz, 1H), 2.52 (s, 3H), 2.37 (s, 3H).

5-Chloro-7-methyl-1-tosyl-1H-indole-4-carbaldehyde

To a solution of (5-chloro-7-methyl-1-tosyl-1H-indol-4-yl)methanol (3.3 g, 9.5 mmol) and N-ethyl-diisopropylamine (8.3 mL, 47.3 mmol) in CH 2 Cl 2 (20 mL)/DMSO (1 mL) was added SO 3 .Py (4.5 g, 28.4 mmol) at 0° C. The mixture was stirred at 0° C. for 2.5 h, and then stirred at room temperature for 15 h. The reaction was quenched by MeOH. The mixture was stirred for 1 h. The mixture was partially concentrated. The mixture was diluted with H 2 O, and then the resulted solid was collected by filtration. The resulting residue was triturated with MeOH to give the title compound. 1 H NMR (400 MHz, ACETONITRILE-d 3 ) δ 10.56 (s, 1H), 8.00 (d, J=3.80 Hz, 1H), 7.62 (d, J=3.80 Hz, 1H), 7.60 (d, J=8.60 Hz, 2H), 7.35 (d, J=8.60 Hz, 2H), 7.22 (s, 1H), 2.60 (s, 3H), 2.37 (s, 3H).

(±)-5-Ethyl-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole

To a suspension of (±)-5-chloro-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole (Example 47-D) (200 mg, 0.46 mmol), cesium carbonate (601 mg, 1.8 mmol), potassium ethylrifluoroborate (125 mg, 0.92 mmol) in dioxane (3 mL)/H 2 O (0.3 mL) Pd(OAc) 2 (21 mg, 0.092 mmol) and Ru-Phos (CAS 787618-22-8, 86 mg, 0.18 mmol) were added and then the mixture was stirred at 90° C. for 15 h. The reaction mixture was cooled to room temperature, and diluted with CH 2 Cl 2 . The organic phase was separated and washed with H 2 O, and brine, dried over Na 2 SO 4 , and then filtered. Concentration of the filtrate gave a residue that was purified by SiO 2 column chromatography (heptane/EtOAc=1/0 to 3/2) to give the title compound. 1 H NMR (400 MHz, ACETONITRILE-d 3 ) δ 7.75 (d, J=3.79 Hz, 1H), 7.57 (d, J=8.34 Hz, 2H), 7.31 (d, J=8.34 Hz, 2H), 6.95 (s, 1H), 6.91 (d, J=3.79 Hz, 1H), 4.90 (d, J=11.24 Hz, 1H), 4.65 (d, J=11.24 Hz, 1H), 4.61-4.64 (m, 1H), 3.79-3.92 (m, 1H), 3.41-3.54 (m, 1H), 2.71 (q, J=7.58 Hz, 2H), 2.53 (s, 3H), 2.35 (s, 3H), 1.56-1.75 (m, 2H), 1.38-1.56 (m, 4H), 1.16 (t, J=7.58 Hz, 3H).

(5-Ethyl-7-methyl-1-tosyl-1H-indol-4-yl)methanol

The title compound was synthesized by deprotection of (±)-5-ethyl-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole as described in Example 47-E. 1 H NMR (400 MHz, ACETONITRILE-d 3 ) δ 7.76 (d, J=3.79 Hz, 1H), 7.58 (d, J=8.59 Hz, 2H), 7.31 (d, J=8.59 Hz, 2H), 6.94 (d, J=3.79 Hz, 1H), 6.91-6.93 (m, 1H), 4.76 (d, J=5.31 Hz, 2H), 2.92 (t, J=5.37 Hz, 1H), 2.72 (q, J=7.58 Hz, 2H), 2.52 (s, 3H), 2.35 (s, 3H), 1.17 (t, J=7.58 Hz, 3H).

5-Ethyl-7-methyl-1-tosyl-1H-indole-4-carbaldehyde

The title compound was synthesized by oxidation of (5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)methanol as described in Example 47-F. MS (ESI+) m/z 342.1 (M+H).

5-Cyclopropyl-7-methyl-1-tosyl-1H-indole-4-carbaldehyde

The title compound was synthesized starting from 5-chloro-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole as described in Example 48-A to 48-C using potassium cyclopropyltrifluoroborate in place of potassium ethylrifluoroborate in Example 48-A. MS (ESI+) m/z 354.2 (M+H).

(±)-5-Isobutyl-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole

To a solution of (±)-5-chloro-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole (Example 47-D) (2.7 g, 6.2 mmol) in isobutylzinc(II) bromide in THF (0.5 M, 24.9 mL, 12.4 mmol) was added Pd[(t-Bu) 3 P] 2 (0.5 g, 0.98 mmol), and then the mixture was stirred at 70° C. for 14 h. The mixture was then stirred under reflux for 7 h. The reaction was then diluted with H 2 O and EtOAc. The mixture was then filtered through a Celite® pad. The filtrate was partitioned. The organic phase was washed with H 2 O, and brine, dried over Na 2 SO 4 , filtered and concentrated. The resulting residue was purified by SiO 2 column chromatography (heptane/EtOAc=88/12) to afford the title compound. 1 H NMR (400 MHz, ACETONITRILE-d 3 ) δ 7.74 (d, J=3.79 Hz, 1H), 7.58 (d, J=8.59 Hz, 2H), 7.31 (d, J=8.60 Hz, 2H), 6.86-6.94 (m, 2H), 4.90 (d, J=11.12 Hz, 1H), 4.64 (d, J=11.12 Hz, 1H), 4.60-4.64 (m, 1H), 3.81-3.91 (m, 1H), 3.45-3.54 (m, 1H), 2.57 (d, J=7.33 Hz, 2H), 2.52 (s, 3H), 2.35 (s, 3H), 1.79-1.88 (m, 1H), 1.56-1.75 (m, 2H), 1.39-1.55 (m, 4H), 0.84-0.89 (m, 6H).

5-Isobutyl-7-methyl-1-tosyl-1H-indole-4-carbaldehyde

The title compound was synthesized as described in Example 47-E and 47-F from (±)-5-isobutyl-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole. MS (ESI+) m/z 370.2 (M+H).

5-Isopropyl-7-methyl-1-tosyl-1H-indole-4-carbaldehyde and 7-methyl-5-propyl-1-tosyl-1H-indole-4-carbaldehyde

A mixture of 5-isopropyl-7-methyl-1-tosyl-1H-indole-4-carbaldehyde and 7-methyl-5-propyl-1-tosyl-1H-indole-4-carbaldehyde, isolated as a 5:1 mixture respectively, were synthesized by a coupling reaction of 5-chloro-7-methyl-1-tosyl-1H-indole-4-carbaldehyde (Example 47-F) with isopropylzinc(II) bromide following the procedure in Example 49-A. MS (ESI+) m/z 356.2 (M+H).

(±)-7-Methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-5-vinyl-1H-indole

To a suspension of (±)-5-chloro-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole (Example 47-D) (2.1 g, 4.8 mmol), vinylboronic anhydride pyridine complex (3.5 g, 14.5 mmol) and K 2 CO 3 (6.7 g, 48.4 mmol) in toluene (10 mL)/H 2 O (4 mL) were added Pd(OAc) 2 (0.22 g, 0.97 mmol) and S-Phos (CAS; 657408-07-6) (0.80 g, 1.9 mmol), and then the mixture was stirred at 90° C. under N 2 atmosphere for 4 h. The reaction mixture was cooled to room temperature, diluted with CH 2 Cl 2 and partitioned. The organic phase was washed with H 2 O and brine, dried over Na 2 SO 4 , and then filtered. Concentration of the filtrate gave a residue that was purified by SiO 2 column chromatography (heptane/EtOAc=95/5 to 7/3) to give the title compound. 1 H NMR (400 MHz, ACETONITRILE-d 3 ) δ 7.78 (d, J=3.79 Hz, 1H), 7.58 (d, J=8.59 Hz, 2H), 7.26-7.38 (m, 3H), 7.13 (dd, J=11.12, 17.43 Hz, 1H), 6.95 (d, J=3.79 Hz, 1H), 5.70 (dd, J=1.26, 17.43 Hz, 1H), 5.31 (dd, J=1.26, 11.12 Hz, 1H), 4.93 (d, J=11.37 Hz, 1H), 4.72 (d, J=11.37 Hz, 1H), 4.56-4.66 (m, 1H), 3.78-3.92 (m, 1H), 3.35-3.57 (m, 1H), 2.57 (s, 3H), 2.35 (s, 3H), 1.56-1.75 (m, 2H), 1.38-1.56 (m, 4H).

7-Methyl-1-tosyl-5-vinyl-1H-indole-4-carbaldehyde

The title compound was synthesized following Example 47-E and 47-F from (±)-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-5-vinyl-1H-indole. MS (ESI+) m/z 340.1 (M+H).

(±)-1-(7-Methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indol-5-yl)ethane-1,2-diol

To a suspension of (±)-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-5-vinyl-1H-indole (1.8 g, 4.2 mmol) in tert-BuOH (70 mL)/H 2 O (70 mL) was added AD-mix-alpha (5 g, 4.2 mmol), and then the mixture was stirred at room temperature for 24 h. The reaction was quenched by aq. Na 2 S 2 O 3 , and the whole mixture was stirred for 0.25 h. The mixture was diluted with CH 2 Cl 2 and partitioned. The organic phase was washed with H 2 O and brine, dried over Na 2 SO 4 , filtered and concentrated. The resulting residue was purified by SiO 2 column chromatography (CH 2 Cl 2 /MeOH=94/6) to give the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.84 (d, J=3.79 Hz, 1H), 7.62 (d, J=8.34 Hz, 2H), 7.40 (d, J=8.34 Hz, 2H), 7.18 (s, 1H), 6.95-6.98 (m, 1H), 5.14 (dd, J=3.92, 6.95 Hz, 1H), 4.69-5.03 (m, 3H), 4.52-4.68 (m, 2H), 3.74-3.92 (m, 1H), 3.44-3.55 (m, 1H), 2.46 (s, 3H), 2.34 (s, 3H), 1.34-1.74 (m, 6H).

(±)-7-Methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole-5-carbaldehyde

To a suspension of (±)-1-(7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indol-5-yl)ethane-1,2-diol (238 mg, 0.52 mmol) in THF (5 mL)/H 2 O (1 mL) was added NaIO 4 (443 mg, 2.1 mmol) at 0° C., and then the mixture was stirred at 0° C. for 1.25 h. The reaction mixture was diluted with EtOAc. The bi-layer was partitioned. The organic phase was washed with half satd. Na 2 S 2 O 3 , H 2 O and brine, dried over Na 2 SO 4 , and then filtered. Concentration of the filtrate gave the title compound with no need of any further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.35 (s, 1H), 8.02 (d, J=4.04 Hz, 1H), 7.68 (d, J=8.59 Hz, 2H), 7.55 (s, 1H), 7.43 (d, J=8.59 Hz, 2H), 7.20 (d, J=4.04 Hz, 1H), 5.27 (d, J=11.62 Hz, 1H), 5.09 (d, J=11.62 Hz, 1H), 4.69-4.76 (m, 1H), 3.68-3.81 (m, 1H), 3.37-3.51 (m, 1H), 2.52 (s, 3H), 2.36 (s, 3H), 1.53-1.70 (m, 2H), 1.32-1.53 (m, 4H).

(±)-(7-Methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indol-5-yl)methanol

A suspension of (±)-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole-5-carbaldehyde (221 mg, 0.52 mmol) and NaBH 4 (98 mg, 2.6 mmol) in EtOH (5 mL) was stirred at 0° C. for 0.5 h. The reaction mixture was diluted with CH 2 Cl 2 . The mixture was washed with H 2 O, half satd. KHSO 4 aqueous solution, H 2 O, and brine, dried over Na 2 SO 4 , and then filtered. Concentration of the filtrate gave the title compound, which was used in the next reaction without any further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.83 (d, J=3.79 Hz, 1H), 7.60 (d, J=8.34 Hz, 2H), 7.38 (d, J=8.34 Hz, 2H), 7.14 (s, 1H), 6.98 (d, J=3.79 Hz, 1H), 5.01 (t, J=5.56 Hz, 1H), 4.87 (d, J=11.37 Hz, 1H), 4.67 (d, J=11.37 Hz, 1H), 4.55-4.63 (m, 3H), 3.73-3.85 (m, 1H), 3.37-3.51 (m, 1H), 2.34 (s, 3H), 2.08 (s, 3H), 1.51-1.71 (m, 2H), 1.30-1.51 (m, 4H).

(7-Methyl-1-tosyl-5-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)-1H-indol-4-yl)methanol

To a solution (±)-(7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indol-5-yl)methanol (200 mg, 0.466 mmol) and iPr 2 EtN (0.16 mL, 0.93 mmol) in CH 2 Cl 2 (2 mL) was added SEMCl (0.124 mL, 0.69 mmol), and then the mixture was stirred at 40° C. for 1 hr. The reaction mixture was concentrated (during the concentration, the THP group was partially removed) and then purified by SiO 2 column chromatography (heptane/EtOAc=1/0 to 1/3) to give the title compound. 1 H NMR (400 MHz, ACETONITRILE-d 3 ) δ 7.81 (d, J=3.79 Hz, 1H), 7.58 (d, J=8.30 Hz, 2H), 7.32 (d, J=8.30 Hz, 2H), 7.08 (s, 1H), 6.99 (d, J=3.79 Hz, 1H), 4.79 (d, J=5.81 Hz, 2H), 4.68 (s, 2H), 4.67 (s, 2H), 3.54-3.63 (m, 2H), 3.05 (t, J=5.80 Hz, 1H), 2.54 (s, 3H), 2.35 (s, 3H), 0.82-0.96 (m, 2H), 0.01 (s, 9H).

7-Methyl-1-tosyl-5-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)-1H-indole-4-carbaldehyde

The title compound was synthesized by oxidation of (7-methyl-1-tosyl-5-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)-1H-indol-4-yl)methanol as described in Example 47-F. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.51 (s, 1H), 8.08 (d, J=3.79 Hz, 1H), 7.64 (d, J=8.34 Hz, 2H), 7.58 (d, J=3.79 Hz, 1H), 7.41 (d, J=8.34 Hz, 2H), 7.26 (s, 1H), 4.94 (s, 2H), 4.70 (s, 2H), 3.47-3.55 (m, 2H), 2.56 (s, 3H), 2.35 (s, 3H), 0.76-0.84 (m, 2H), 0.05 (s, 9H).

2-((4-(Hydroxymethyl)-7-methyl-1-tosyl-1H-indol-5-yl)methyl)isoindoline-1,3-dione

To a solution of (±)-(7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indol-5-yl)methanol (Example 52-C) (210 mg, 0.49 mmol), phthalimide (144 mg, 0.98 mmol), and PPh 3 (385 mg, 1.47 mmol) in THF (5 mL) was added DIAD (0.29 mL, 1.48 mmol) at 0° C., and then the mixture was stirred at room temperature for 3.5 h. The reaction was then concentrated and partially purified by SiO 2 column chromatography (heptane/EtOAc=1/0 to 6/4). A solution of the resulting residue and 4M HCl in dioxane (4 mL) in MeOH (10 mL) was stirred at room temperature for 0.5 h. The reaction mixture was poured into 5% aq. NaHCO 3 . The basic mixture was extracted with CH 2 Cl 2 . The organics extract was washed with H 2 O and brine, dried over Na 2 SO 4 , and then filtered. Concentration of the filtrate gave a residue which was purified by SiO 2 column chromatography (heptane/EtOAc=6/4 to 3/7) to give the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.76-7.95 (m, 5H), 7.59 (d, J=8.34 Hz, 2H), 7.38 (d, J=8.34 Hz, 2H), 7.06 (d, J=4.04 Hz, 1H), 6.90 (s, 1H), 5.08 (t, J=5.31 Hz, 1H), 4.91 (s, 2H), 4.85 (d, J=5.31 Hz, 2H), 2.38 (s, 3H), 2.33 (s, 3H).

5-((1,3-Dioxoisoindolin-2-yl)methyl)-7-methyl-1-tosyl-1H-indole-4-carbaldehyde

A suspension of 2-((4-(hydroxymethyl)-7-methyl-1-tosyl-1H-indol-5-yl)methyl)isoindoline-1,3-dione (180 mg, 0.38 mmol) and MnO 2 (165 mg, 1.9 mmol) in toluene (20 mL) was stirred at 80° C. for 11 h. The reaction mixture was cooled to room temperature. The reaction mixture was filtered off through Celite®. The Celite® cake was washed with CH 2 Cl 2 . The combined filtrate was concentrated to give the title compound, with no need of further purification. MS (ESI+) m/z 473.1 (M+H).

(±)-5-(Methoxymethyl)-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole

To a solution of (±)-(7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indol-5-yl)methanol (Example 52-C) (170 mg, 0.40 mmol) in DMF (1 mL) was added NaH (31.7 mg, 60% in mineral oil, 0.79 mmol) at room temperature, and then the mixture was stirred for 10 min. To the mixture was added MeI (25 uL, 0.40 mmol) at room temperature, and then the mixture was stirred for 2.5 h. The reaction was quenched by half saturated aqueous solution of KHSO 4 , and diluted with EtOAc. The bi-layer was partitioned. The organic phase was washed successively H 2 O and brine, dried over Na 2 SO 4 , and then filtered. Concentration of the filtrate gave the title compound, without need of any further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.86 (d, J=3.79 Hz, 1H), 7.62 (d, J=8.34 Hz, 2H), 7.39 (d, J=8.34 Hz, 2H), 7.08 (s, 1H), 6.99 (d, J=3.79 Hz, 1H), 4.87 (d, J=11.37 Hz, 1H), 4.67 (d, J=11.37 Hz, 1H), 4.60-4.64 (m, 1H), 4.44-4.54 (m, 2H), 3.73-3.86 (m, 1H), 3.41-3.52 (m, 1H), 3.30 (s, 3H), 2.47 (s, 3H), 2.34 (s, 3H), 1.51-1.78 (m, 2H), 1.34-1.51 (m, 4H).

5-(Methoxymethyl)-7-methyl-1-tosyl-1H-indole-4-carbaldehyde

The title compound was synthesized from (±)-5-(methoxymethyl)-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole following Example 47-E and 47-F. MS (ESI+) m/z 358.1 (M+H).

5-Bromo-7-methyl-1H-indole-4-carbonitrile

The title compound was synthesized from 2-bromo-4-methyl-5-nitrobenzonitrile (CAS; 1202858-65-8) as described in Example 47-C. MS (ES) m/z 233.1, 235.1. (M−H).

5-Bromo-7-methyl-1-tosyl-1H-indole-4-carbonitrile

The title compound was synthesized from 5-bromo-7-methyl-1H-indole-4-carbonitrile as described in Example 47-D. MS (ESI−) m/z 387.2, 389.2. (M−H).

5-Bromo-7-methyl-1-tosyl-1H-indole-4-carbaldehyde

To a solution of 5-bromo-7-methyl-1H-indole-4-carbonitrile (3.2 g, 8.2 mmol) in 80 mL of toluene (80 mL) at −78° C., diisobutylaluminium hydride in toluene solution (1M, 9.7 mL, 9.7 mmol) was added slowly. The mixture was stirred at −78° C. for 30 min, and then −60° C. for 30 min. The reaction was quenched by 1N aqueous HCl solution (10 mL) at −60° C., then was warmed to 0° C. At this point, 1N aqueous HCl (40 mL) was added. The reaction mixture was stirred for 30 min at room temperature and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The resulting residue was purified by SiO 2 column chromatography [heptane/(30% EtOAc in CH 2 Cl 2 )=1/0 to 0/1] to give the title compound. 1 H NMR (400 MHz, DICHLOROMETHANE-d 2 ) δ 10.47 (s, 1H), 7.95 (d, J=3.8 Hz, 1H), 7.68 (d, J=3.8 Hz, 1H), 7.54 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.5 Hz, 2H), 7.27 (s, 1H), 2.59 (s, 3H), 2.38 (s, 3H).

Intermediate 2

4,5-Diamino-2-fluorobenzonitrile

To a solution of 2,4-difluoro-5-nitrobenzonitrile (CAS #: 67152-20-9) (5.0 g, 27.2 mmol) in EtOH (100 mL) was added NH 4 OH (100 mL) slowly at room temperature. The mixture was stirred for 30 min, then concentrated under reduced pressure to about 100 mL. The yellow product was filtered and washed with water, and then dried. To a solution of the residue (3.96 g, 22 mmol) in EtOAc (150 mL) and acetic acid (25 mL) was added zinc (14.3 g, 219 mmol). The mixture was stirred at room temperature for 2 hour. The reaction mixture was diluted with EtOAc and filtered through a pad of Celite®. The Celite® pad was washed with EtOAc. The filtrate was concentrated, and the residue was dissolved in MeOH (50 mL) and NH 4 OH (100 mL). The mixture was then concentrated to around 100 mL and the mixture was left standing at room temperature overnight. The precipitate was filtered and washed with water, and then dried to give the title compound. MS (ESI+) m/z 152.1 (M+H).

6-Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 5-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

A solution of 4,5-diamino-2-fluorobenzonitrile (2.4 g, 15.9 mmol) in formic acid (40 mL) was heated to reflux for 2 hours. The reaction was concentrated. MS (ESI+) m/z 152.1 (M+H).

To a solution of the residue (15.9 mmol) obtained above in DMF (40 mL) was added NaH (60%, 3.2 g, 79 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. Then 2-(trimethylsilyl)ethoxy)methylchloride (3.1 mL, 17.5 mmol) was added. The mixture was stirred at 0° C. for another 2 hours. MeOH (20 mL) was added to the mixture. The mixture was diluted with Et 2 O. The organic layer was separated and washed with water and brine, dried over Na 2 SO 4 , and filtered. Concentration of the filtrate gave a residue, which was purified by flash column chromatography (0% to 100% EtOAc in heptane) to give a mixture of title compounds. 1 H NMR (400 MHz, METHANOL-d4) δ 8.57 (s, 1H), 8.49 (s, 1H), 8.13-8.17 (m, 1H), 8.11 (d, J=5.56 Hz, 1H), 7.69 (d, J=8.84 Hz, 1H), 7.63 (d, J=9.60 Hz, 1H), 5.69 (d, J=10.99 Hz, 4H), 3.50-3.65 (m, 4H), 0.83-0.96 (m, 4H)-0.06 (s, 18H).

Intermediate 3

N-(3-cyano-2-methyl-6-nitrophenyl)acetamide

To a solution of N-(3-cyano-2-methylphenyl)acetamide (CAS #: 70946-79-1) (1.8 g, 10.33 mmol) in conc. sulfuric acid (20 mL) at −10° C., potassium nitrate (2.08 g, 20.67 mmol) in 5 mL of conc. sulfuric acid was added slowly. After addition, the reaction was stirred at −10° C. for 30 min, then at 0° C. for 3.5 hr. The reaction mixture was poured onto ice, and then the precipitate was collected by filtration. The solid was washed with water and then purified by silica gel flash column chromatography (heptanes/EtOAc=1/0 to 1/1) to give the title compound. MS (ESI−) m/z 218.0 (M−H).

3-Amino-2-methyl-4-nitrobenzonitrile

N-(3-cyano-2-methyl-6-nitrophenyl)acetamide (0.37 g, 1.7 mmol) was added to a 2N aq. H 2 SO 4 solution (10 mL). The reaction was heated to 100° C. for 6 hr. The reaction mixture was cooled to rt and poured into iced water. The solid precipitate was collected by filtration, and then washed with water several times to give the title compound. MS (ESI−) m/z 176.1 (M−H).

3,4-Diamino-2-methylbenzonitrile

To a solution of 3-amino-2-methyl-4-nitrobenzonitrile (250 mg, 1.41 mmol) in methanol (15 mL), palladium-activated carbon ethylene diamine complex (255 mg, 3.5%-6.5% Pd, 0.071 mmol) was added. The reaction was stirred at rt under hydrogen atmosphere for 2 hr. The catalyst was removed by filtration through Celite® pad. The Celite® pad was washed with MeOH. The collected filtrate was concentrated to give the title compound. MS (ESI+) m/z 148.0 (M+H).

4-(2,2-Dibromovinyl)-5,7-dimethyl-1-tosyl-1H-indole

To a solution of 5,7-dimethyl-1-tosyl-1H-indole-4-carbaldehyde (Example 46-D) (1.5 g, 4.58 mmol) and CBr 4 (3.04 g, 9.16 mmol) in CH 2 Cl 2 (50 mL) was added PPh 3 (3.61 g, 13.74 mmol) at 0° C., and then the mixture was stirred at room temperature for 1 hr. The reaction mixture was directly purified by silica gel flash chromatography (heptanes/EtOAc=1/0 to 1/1) to give the title compound. MS (ESI+) m/z 483.9, 485.9, 481.9, 487.1 (M+H).

2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

A solution of 4-(2,2-dibromovinyl)-5,7-dimethyl-1-tosyl-1H-indole (130 mg, 0.269 mmol), 3,4-diaminobenzonitrile (46.6 mg, 0.350 mmol), and DABCO (75 mg, 0.673 mmol) in NMP (0.5 mL) was stirred at 100° C. for 19 h. The reaction mixture was cooled to room temperature. The reaction mixture was concentrated and purified by silica gel flash column chromatography (heptanes/EtOAc=1/3 to 0/1) to give the title compound. MS (ESI+) m/z 455.2 (M+H).

2-((5,7-Dimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

A mixture of 2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (370 mg, 0.814 mmol), KOH (457 mg, 8.14 mmol), and isoamylamine (1.892 mL, 16.28 mmol) in EtOH (15 mL) was stirred at 100° C. under microwave irradiation for 2 hr. The reaction mixture was diluted with CH 2 Cl 2 . The mixture was filtered through SiO 2 pad. The SiO 2 cake was washed with a mixture of CH 2 Cl 2 /MeOH (c.a. 6/1). The organic solution was concentrated and purified by silica gel flash column chromatography [(5% 2,2,2-trifluoroethanol in CH 2 Cl 2 )/MeOH=1/0 to 85/15] to give the title compound. 1 H NMR (400 MHz, DMSO-d 6 , with about 5 μL TFA) δ ppm 11.01 (br. s., 1H), 8.05 (s, 1H), 7.67 (br. d, J=8.30 Hz, 1H), 7.62 (br. d, J=8.30 Hz, 1H), 7.26 (t, J=2.80 Hz, 1H), 6.79 (s, 1H), 6.43 (dd, J=1.80, 2.80 Hz, 1H), 4.53 (s, 2H), 2.43 (s, 3H), 2.35 (s, 3H). HRMS calcd. for C 19 H 16 N 4 (M+H) + 301.1448. found 301.1459.

2-((7-Methyl-1-tosyl-5-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from 7-methyl-1-tosyl-5-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)-1H-indole-4-carbaldehyde (Example 52-A) analogously to Example 58-B. MS (ESI+) m/z 601.3 (M+H).

2-((5-(Hydroxymethyl)-7-methyl-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of 2-((7-methyl-1-tosyl-5-(((2-(trimethylsilyl)ethoxy)methoxy)methyl)-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (133 mg, 0.221 mmol) in CH 2 Cl 2 (10 mL) was added BF 3 -OEt 2 (0.084 mL, 0.664 mmol) at 0° C. The whole mixture was stirred at 0° C. for 1.5 h, and then at room temperature for 2.5 h. The reaction was quenched by 5% aq. NaHCO 3 and stirred for 0.5 h. The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 . The organic layers were combined and washed with H 2 O and brine, dried over Na 2 SO 4 , and filtered. Concentration of the filtrate gave the title compound, without need of further purification. MS (ESI+) m/z 471.1 (M+H).

2-((5-(Hydroxymethyl)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized by a deprotection of 2-((5-(hydroxymethyl)-7-methyl-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile analogously to Example 58-C. 1 H NMR (400 MHz, DMSO-d 6 with about 5 μL TFA) δ ppm 11.10 (br. s., 1H), 8.08 (s, 1H), 7.69 (d, J=8.60 Hz, 1H), 7.62 (dd, J=1.50, 8.60 Hz, 1H), 7.30 (dd, J=2.80, 3.00 Hz, 1H), 6.97 (s, 1H), 6.53 (dd, J=1.77, 3.03 Hz, 1H), 4.67 (s, 2H), 4.63 (s, 2H), 2.45 (s, 3H). HRMS calcd. for C 13 H 16 N 4 O (M+H) + 317.1397. found 317.1407.

2-((5-((1,3-Dioxoisoindolin-2-yl)methyl)-7-methyl-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from 5-((1,3-dioxoisoindolin-2-yl)methyl)-7-methyl-1-tosyl-1H-indole-4-carbaldehyde (Example 53-B) analogously to Example 58-B. MS (ESI+) m/z 600.1 (M+H).

2-((5-(Aminomethyl)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

A mixture of 2-((5-((1,3-dioxoisoindolin-2-yl)methyl)-7-methyl-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (60 mg, 0.100 mmol) and hydrazine hydrate (5.01 mg, 0.100 mmol) in EtOH (2 mL) was stirred at 100° C. under microwave irradiation for 0.5 hr. To the mixture was added KOH (56.1 mg, 1.001 mmol), and then the mixture was stirred at 100° C. under the microwave irradiation for 1.75 h. The reaction mixture was diluted with CH 2 Cl 2 /2,2,2-trifluoroethanol (c.a. 9/1). The layers were separated and the organic layer was washed successively by H 2 O and brine, dried over Na 2 SO 4 , and filtered. After concentration, the residue was purified by silica gel flash column chromatography (CH 2 Cl 2 /2M NH 3 in MeOH=94/6) to give the title compound. 1 H NMR (400 MHz, DMSO-d 6 with about 5 μL TFA) δ ppm 11.28 (br. s., 1H), 8.53 (br. s., 3H), 8.09 (s, 1H), 7.68 (d, J=8.34 Hz, 1H), 7.55 (dd, J=1.00, 8.30 Hz, 1H), 7.38 (t, J=2.80 Hz, 1H), 7.06 (s, 1H), 6.76-6.84 (m, 1H), 4.61 (s, 2H), 4.27-4.42 (m, 2H), 2.45 (s, 3H). HRMS calcd. for C 19 H 17 N 6 (M+H) + 316.1557. found 316.1559.

N-((4-((5-cyano-1H-benzo[d]imidazol-2-yl)methyl)-7-methyl-1H-indol-5-yl)methyl)acetamide

To a mixture of 2-((5-(aminomethyl)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (20 mg, 0.063 mmol) in CH 2 Cl 2 (1 mL)/5% aq. NaHCO 3 (2 mL) was added acetyl chloride (45 μL, 0.634 mmol), and then the mixture was stirred at room temperature for 1 hr. The reaction was quenched by methylamine in EtOH (33%, 2 mL), and then stirred for 0.5 h. The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 . The combined organics were washed with H 2 O and brine, dried over Na 2 SO 4 , and filtered. After concentration the residue was purified by silica gel flash column chromatography (CH 2 Cl 2 /2M NH 3 in MeOH=94/6) to give the title compound. 1 H NMR (400 MHz, DMSO-d 6 with about 5 μL TFA) δ ppm 11.16 (br. s., 1H), 8.47 (t, J=5.31 Hz, 1H), 8.10 (s, 1H), 7.69 (d, J=8.30 Hz, 1H), 7.65 (dd, J=1.00, 8.30 Hz, 1H), 7.30 (dd, J=2.80, 3.00 Hz, 1H), 6.91 (s, 1H), 6.49 (dd, J=1.80, 3.00 Hz, 1H), 4.64 (s, 2H), 4.42 (d, J=5.31 Hz, 2H), 2.45 (s, 3H), 1.79 (s, 3H). HRMS calcd. for C 21 H 19 N 5 O (M+H) + 358.1662. found 358.1660.

5-Bromo-2-((5,7-dimethyl-1H-indol-4-yl)methyl)-7-fluoro-1H-benzo[d]imidazole

The title compound was synthesized using 5-bromo-3-fluorobenzene-1,2-diamine (CAS: 517920-69-3) analogously to Example 58-B. MS (ESI+) m/z 372.0, 374.0 (M+H).

2-((5,7-Dimethyl-1H-indol-4-yl)methyl)-7-fluoro-1H-benzo[d]imidazole-5-carbonitrile

Zinc cyanide (44 mg, 0.375 mmol) was weighed into a 50 mL flask, a degassed solution of 5-bromo-2-((5,7-dimethyl-1H-indol-4-yl)methyl)-7-fluoro-1H-benzo[d]imidazole (45 mg, 0.121 mmol) in DMF (4 mL) was added followed by Pd(Ph 3 P) 4 (14 mg, 0.012 mmol). The reaction mixture was heated at 120° C. for 2 hours. Additional portions of zinc dust, dppf, and Pd 2 (dba) 3 were added followed by heating to 130° C. until no starting material remained by LC-MS. The reaction was diluted with EtOAc and a saturated solution of NaHCO 3 , then filtered through a Celite® pad. The filtrate was extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated to dryness. The residue was purified by reverse phase HPLC (HC-B) to afford the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.98 (br. s., 1H) 7.78 (s, 1H) 7.52-7.67 (m, 1H) 7.48 (d, J=10.61 Hz, 1H) 7.24 (t, J=2.78 Hz, 1H) 6.76 (s, 1H) 6.46 (dd, J=3.03, 2.02 Hz, 1H) 4.44 (s, 2H) 2.41 (s, 3H) 2.36 (s, 3H). HRMS calculated for C 19 H 15 FN 4 (M+H) + 319.1354. found 319.1361.

The following compounds were prepared with similar method as described in Example 58 using the appropriate aldehydes and dianilines.

(±)-2-((5,7-Dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (110 mg, 0.402 mmol) in THF (2 mL), 2 M LDA in heptane/THF/ethylbenzene (0.221 mL, 0.443 mmol) was added at −78° C. After stirring for 45 min., a solution of 5,7-dimethyl-1-tosyl-1H-indole-4-carbaldehyde (Example 46-D) (132 mg, 0.402 mmol) in THF (2 mL) was added to the reaction mixture at the same temperature. After stirring for 1 h, the reaction mixture was diluted with MeOH (0.1 mL), aq. NH 4 Cl (0.5 mL), brine (3 mL) and EtOAc (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (CH 2 Cl 2 /MeOH=100:0 to 50:50) to give title compounds as a mixture. MS (ESI+) m/z 601.1 (M+H).

(±)-2-((5,7-Dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (90 mg, 0.150 mmol) in CH 2 Cl 2 (1.5 mL), BF 3 .OEt 2 (0.095 mL, 0.749 mmol) was added at 0° C. After stirring for 5 min., the mixture was warmed to room temperature. After stirring for 1 h, the reaction mixture was diluted with 2M aq. Na 2 CO 3 and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated to give the title compound, without need of further purification. MS (ESI+) m/z 471 (M+H).

a) (±)-2-((5,7-Dimethyl-1H-indol-4-yl)(hydroxy)methyl)benzo[d]imidazole-5-carbonitrile

A mixture of (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile, KOH (84 mg, 1.50 mmol) and isoamylamine (0.35 mL, 3 mmol) in EtOH (1.5 mL) was heated at 100° C. for 1 h under the microwave irradiation. The reaction mixture was concentrated. The residue was diluted with CH 2 Cl 2 and brine. The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 . The combined organic extracts were dried over NaSO 3 , filtered and evaporated. The resulting residue was purified by flash column chromatography on NH-modified silica gel (CH 2 Cl 2 :MeOH=100:0 to 10:1) to give the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.90 (br.s, 1H) 10.84 (s, 1H) 7.87-7.91 (m, 1H) 7.56-7.61 (m, 1H) 7.45-7.50 (m, 1H) 7.14 (t, J=2.65 Hz, 1H) 6.71 (s, 1H) 6.44-6.45 (m, 1H) 6.35-6.36 (m, 1H) 2.43 (s, 3H) 2.39 (s, 3H). HRMS calcd. for C 22 H 20 N 5 O (M+H) + 317.1397. found 317.1404.

b) (+) and (−)-2-((5,7-dimethyl-1H-indol-4-yl)(hydroxy)methyl)benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-((5,7-dimethyl-1H-indol-4-yl)(hydroxy)methyl)benzo[d]imidazole-5-carbonitrile was achieved by chiral HPLC using a CHIRALCEL® OD-H column with 20% MeOH and 20% EtOH in heptane to give (+)-2-((5,7-dimethyl-1H-indol-4-yl)(hydroxy)methyl)benzo[d]imidazole-5-carbonitrile (t r =4.8 min) and (−)-2-((5,7-dimethyl-1H-indol-4-yl)(hydroxy)methyl)benzo[d]imidazole-5-carbonitrile (t r =9.3 min).

7-(±)-Methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-5-(((triisopropylsilyl)oxy)methyl)-1H-indole

To a solution of (±)-(7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indol-5-yl)methanol (Example 52-C) (1 g, 2.30 mmol) in DMF (10 mL) was added imidazole (239 mg, 3.51 mmol), followed by TIPSCI (0.496 mL, 2.339 mmol). The whole mixture was stirred at room temperature for 24 h. The reaction was then quenched by MeOH. The mixture was then stirred at room temperature for 0.25 h. The mixture was then diluted with EtOAc. The organic phase was successively washed with H 2 O and brine, dried over Na 2 SO 4 , filtered, and concentrated. The resulting residue was purified by SiO 2 chromatography (heptane/EtOAc=1/0 to 7/3) to afford the title compound. 1 H NMR (400 MHz, ACETONITRILE-d 3 ) δ 7.76 (d, J=3.92 Hz, 1H), 7.56 (d, J=8.34 Hz, 2H), 7.29 (d, J=8.34 Hz, 2H), 7.24 (s, 1H), 6.93 (d, J=3.92 Hz, 1H), 4.94 (s, 2H), 4.89 (d, J=11.62 Hz, 1H), 4.69 (d, J=11.62 Hz, 1H), 4.57 (s, 1H), 3.72-3.88 (m, 1H), 3.38-3.54 (m, 1H), 2.56 (s, 3H), 2.34 (s, 3H), 1.35-1.74 (m, 6H), 1.11-1.22 (m, 3H), 1.00-1.10 (m, 18H).

7-Methyl-1-tosyl-5-(((triisopropylsilyl)oxy)methyl)-1H-indole-4-carbaldehyde

The title compound was prepared from 7-(±)-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-5-(((triisopropylsilypoxy)methyl)-1H-indole following the procedures shown in Example 47-E and 47-F. MS (ESI+) m/z 500.3 (M+H).

(±)-2-(hydroxy(7-methyl-1-tosyl-5-(((triisopropylsilyl)oxy)methyl)-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(hydroxy(7-methyl-1-tosyl-5-(((triisopropylsilyl)oxy)methyl)-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

A mixture of title compounds was synthesized from 7-methyl-1-tosyl-5-(((triisopropylsilypoxy)methyl)-1H-indole-4-carbaldehyde analogously to Example 64-A. MS (ESI+) m/z 773.4 (M+H).

a) (±)-2-(Hydroxy(5-(hydroxymethyl)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of (±)-2-(hydroxy(7-methyl-1-tosyl-5-(((triisopropylsilypoxy)methyl)-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(hydroxy(7-methyl-1-tosyl-5-(((triisopropylsilypoxy)methyl)-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (263 mg, 0.340 mmol) in CH 2 Cl 2 (10 mL) was added BF 3 —OEt 2 (0.215 mL, 1.70 mmol) at 0° C., and then the mixture was stirred at room temperature for 2.5 h. The reaction was quenched by 7N NH 3 in MeOH. The mixture was filtered off through SiO 2 . The SiO 2 cake was washed with CH 2 Cl 2 /MeOH (c.a. 6/1). Combined organics were concentrated. The resulting residue was mixed with isoamylamine (148 mg, 1.70 mmol), and KOH (95 mg, 1.70 mmol) in EtOH (10 mL) and stirred at 100° C. under microwave irradiation for 1 hr. The reaction mixture was diluted with CH 2 Cl 2 . The mixture was filtered through SiO 2 . The SiO 2 cake was washed with a mixture of CH 2 Cl 2 /MeOH (c.a. 6/1). The filtrate was concentrated and purified by RP-HPLC (HC-A) to give the title compound. 1 H NMR (400 MHz, ACETONITRILE-d 3 with about 5 μL TFA) δ ppm 9.46 (br. s., 1H), 8.08-8.19 (m, 1H), 7.86 (d, J=8.60 Hz, 1H), 7.80 (dd, J=1.30, 8.60 Hz, 1H), 7.27 (dd, J=2.80, 3.00 Hz, 1H), 7.02 (s, 1H), 6.89 (s, 1H), 6.71 (dd, J=2.02, 3.00 Hz, 1H), 5.05 (d, J=11.87 Hz, 1H), 4.76 (d, J=11.87 Hz, 1H), 2.48 (s, 3H). HRMS calcd. for C 19 H 16 N 4 O 2 (M+H) + 333.1352. found 333.1352.

b) (+) and (−)-2-(hydroxy(5-(hydroxymethyl)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(hydroxy(5-(hydroxymethyl)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a CHIRALCEL® OD-H column with 35% MeOH in CO 2 to give (+)-2-(hydroxy(5-(hydroxymethyl)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =2.7 min) and (−)-2-(hydroxy(5-(hydroxymethyl)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =4.6 min).

7-Methyl-5-(phenoxymethyl)-1-tosyl-1H-indole-4-carbaldehyde

The title compound was prepared from (±)-(7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indol-5-yl)methanol (Example 52-C) using phenol instead of phthalimide in the method depicted in Example 53. MS (ESI+) m/z 420.1 (M+H).

(±)-2-(Hydroxy(7-methyl-5-(phenoxymethyl)-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(hydroxy(7-methyl-5-(phenoxymethyl)-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

A mixture of title compounds was synthesized from 7-methyl-5-(phenoxymethyl)-1-tosyl-1H-indole-4-carbaldehyde analogously to Example 64-A MS (ESI+) m/z 693.3 (M+H).

(±)-2-(Hydroxy(7-methyl-5-(phenoxymethyl)-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of (±)-2-(hydroxy(7-methyl-5-(phenoxymethyl)-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(hydroxy(7-methyl-5-(phenoxymethyl)-1-tosyl-1H-indol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (160 mg, 0.231 mmol) in CH 2 Cl 2 (2 mL) was added BF 3 —OEt 2 (0.059 mL, 0.462 mmol) at 0° C., and then the mixture was stirred at room temperature for 2.5 h. The reaction was quenched by 7N NH 3 in MeOH. The mixture was filtered off through SiO 2 . The SiO 2 cake was washed with CH 2 Cl 2 /MeOH (c.a. 6/1). The combined organics were concentrated to give the title compound, without need of further purification. MS (ESI+) m/z 563.3 (M+H).

a) (±)-2-((5-(Ethoxymethyl)-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of 2-(hydroxy(7-methyl-5-(phenoxymethyl)-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (130 mg, 0.23 mmol) in EtOH (3 mL), isoamylamine (101 mg, 1.15 mmol), and KOH (64.8 mg, 1.15 mmol) were added and the reaction stirred at 100° C. for 1.5 h under microwave irradiation. The reaction mixture was diluted with CH 2 Cl 2 filtered through SiO 2 . The SiO 2 cake was washed with a mixture of CH 2 Cl 2 /MeOH (c.a. 6/1). The organic solution was concentrated and purified by RP-HPLC (HC-A) to give the title compound. 1 H NMR (400 MHz, ACETONITRILE-d 3 with about 5 μL TFA) δ ppm 9.45 (br. s., 1H), 8.08 (s, 1H), 7.79 (d, J=8.60 Hz, 1H), 7.75 (dd, J=1.30, 8.60 Hz, 1H), 7.25 (dd, J=2.80, 3.00 Hz, 1H), 7.02 (s, 1H), 6.76 (s, 1H), 6.62 (dd, J=2.02, 3.03 Hz, 1H), 4.80 (d, J=10.86 Hz, 1H), 4.63 (d, J=10.86 Hz, 1H), 3.56-3.73 (m, 2H), 2.48 (s, 3H), 1.13 (t, J=6.95 Hz, 3H). HRMS calcd. for C 21 H 20 N 4 O 2 (M+H) + 361.1665. found 361.1658.

b) (+) and (−)-2-((5-(ethoxymethyl)-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-((5-(ethoxymethyl)-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by normal phase HPLC using a CHIRALPAK® AS column with 10% (0.2% diethylamine in EtOH) in heptane to give (−)-2-((5-(ethoxymethyl)-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =18.0 min) and (+)-2-((5-(ethoxymethyl)-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =21.1 min).

The following compounds were prepared with similar method as described in Example 64.

(±)-2-((5,7-Dimethyl-1-tosyl-1H-indol-4-yl)(methoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(methoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

To a suspension of (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 64-A) (22 mg, 0.037 mmol) and NaH (oil dispersion, 60%) (2.93 mg, 0.073 mmol) in THF (0.4 mL), MeI (2.7 μl, 0.044 mmol) was added at 0° C. After stirring for 1.5 h at the same temperature, the mixture was allowed to reach room temperature and then stirred overnight. The mixture was diluted with aq. NH 4 Cl and EtOAc. The layers were separated and the aqueous layer extracted with EtOAc. The combined organic phase was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated to give the mixture of title compounds without need of further purification. MS (ESI+) m/z 615.2 (M+H).

(±)-2-((5,7-Dimethyl-1H-indol-4-yl)(methoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from a mixture of (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(methoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(methoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile as described in Example 64-B and 64-C. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.96 (s, 1H) 7.96 (s, 1H) 7.63 (d, J=8.34 Hz, 1H) 7.53 (d, J=8.34 Hz, 1H) 7.20 (t, J=2.65 Hz, 1H) 6.75 (s, 1H) 6.49 (br.s, 1H) 6.21 (s, 1H) 3.35 (s, 3H) 2.43 (s, 3H) 2.42 (s, 3H). HRMS calcd. for C 20 H 18 N 4 O (M+H) + 331.1553. found 331.1559.

(±)-2-((5-cyano-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1H-indol-4-yl)methoxy)acetic acid

The title compound was synthesized from a mixture of (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 64-A) as described in Example 68 using methyl 2-bromoacetate as electrophile instead of methyl iodide. 1 H NMR (TFA salt, 400 MHz, DMSO-d 6 ) δ ppm 11.00 (br.s, 1H) 7.97 (s, 1H) 7.64 (d, J=8.33 Hz, 1H) 7.51-7.54 (m, 1H) 7.21 (t, J=2.78 Hz, 1H) 6.76 (s, 1H) 6.48-6.51 (m, 2H) 4.14 (A of AB, J=16.55 Hz, 1H) 3.99 (B of AB, J=16.55 Hz, 1H) 2.42 (s, 3H) 2.40 (s, 3H). HRMS calcd. for C 21 H 18 N 4 O 3 (M+H) + 375.1452. found 375.1465.

(±)-2-((5-Ethyl-7-methyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

A mixture of title compounds was synthesized from 5-ethyl-7-methyl-1-tosyl-1H-indole-4-carbaldehyde analogously to Example 64-A. MS (ESI+) m/z 615.4 (M+H).

(±)-2-((5-Ethyl-7-methyl-1-tosyl-1H-indol-4-yl)(methoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)(methoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

To a solution of a mixture of (±)-2-((5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1 g, 1.30 mmol) and MeI (0.122 mL, 1.952 mmol) in DMF (5 mL) was added NaH (60% in mineral oil, 78 mg, 1.952 mmol), and then the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into a mixture of EtOAc/half satd. KHSO 4 . The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic phase was successively washed with H 2 O and brine, dried over Na 2 SO 4 , filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (heptanes/EtOAc 9/1 to 6/4) to give title compounds as a mixture. MS (ESI+) m/z 629.4 (M+H).

(±)-2-((5-Ethyl-7-methyl-1-tosyl-1H-indol-4-yl)(methoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

A mixture of (±)-2-((5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)(methoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile, (±)-2-((5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)(methoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (mixture, 650 mg, 1.03 mmol) and LiBF 4 in CH 3 CN (1M, 10 mL, 10 mmol)/H 2 O (1 mL) was stirred at 75° C. for 14 h. The mixture was cooled to room temperature and poured into 5% NaHCO 3 . The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 . The combined organic phase was successively washed with H 2 O and brine, dried over Na 2 SO 4 , filtered and concentrated. The resulting residue was purified by silica gel flash column chromatography (heptanes/EtOAc=55/45) to give the title compound. MS (ESI+) m/z 499.2 (M+H).

a) (±)-2-((5-Ethyl-7-methyl-1H-indol-4-yl)(methoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from (±)-2-((5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)(methoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile as described in Example 64-C. 1 H NMR (400 MHz, ACETONITRILE-d 3 with about 5 μL TFA) δ ppm 9.33 (br. s., 1H), 7.99 (s, 1H), 7.72 (d, J=8.50 Hz, 1H), 7.68 (dd, J=1.30, 8.50 Hz, 1H), 7.17 (dd, J=2.80, 3.00 Hz, 1H), 6.94 (s, 1H), 6.30 (dd, J=2.02, 3.00 Hz, 1H), 6.26 (s, 1H), 3.42 (s, 3H), 2.73-2.86 (m, 2H), 2.48 (s, 3H), 1.21 (t, J=7.58 Hz, 3H). HRMS calcd. for C 21 H 20 N 4 O (M+H) + 345.171. found 345.1713.

b) (+) and (−)-2-((5-Ethyl-7-methyl-1H-indol-4-yl)(methoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-((5-ethyl-7-methyl-1H-indol-4-yl)(methoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by normal phase chiral HPLC using a CHIRALPAK® AD column with 30% IPA (0.2% diethylamine) in heptane to give (+)-2-((5-ethyl-7-methyl-1H-indol-4-yl)(methoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =5.8 min) and (−)-2-((5-ethyl-7-methyl-1H-indol-4-yl)(methoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile=6.6 min).

a) (±)-2-((5-isobutyl-7-methyl-1H-indol-4-yl)(methoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was prepared with similar method as described in Example 70 starting from 5-Isobutyl-7-methyl-1-tosyl-1H-indole-4-carbaldehyde (Example 49-B). 1 H NMR (400 MHz, DMSO-d 6 with about 5 μL TFA) δ ppm 10.96 (br. s., 1H), 7.96 (s, 1H), 7.63 (d, J=8.34 Hz, 1H), 7.53 (dd, J=1.26, 8.34 Hz, 1H), 7.16 (t, J=2.80 Hz, 1H), 6.75 (s, 1H), 6.42 (dd, J=1.80, 2.80 Hz, 1H), 6.19 (s, 1H), 3.37 (s, 3H), 2.73-2.84 (m, 1H), 2.55-2.65 (m, 1H), 2.43 (s, 3H), 1.81-2.02 (m, 1H), 0.93 (d, J=6.57 Hz, 3H), 0.89 (d, J=6.57 Hz, 3H). HRMS calcd. for C 23 H 24 N 4 O (M+H) + 373.2023. found 373.2025.

b) (+) and (−)-2-((5-isobutyl-7-methyl-1H-indol-4-yl)(methoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-((5-isobutyl-7-methyl-1H-indol-4-yl)(methoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a (R,R)-Whelk-O®1 column with 40% (0.2% diethylamine in EtOH) in heptane to give (+)-2-((5-isobutyl-7-methyl-1H-indol-4-yl)(methoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =5.9 min) and (−)-2-((5-isobutyl-7-methyl-1H-indol-4-yl)(methoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =9.0 min).

(±)-2-((5,7-Dimethyl-1-tosyl-1H-indol-4-yl)(ethoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(ethoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

To a solution of a mixture of (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 64-A) (82 mg, 0.136 mmol) and DIPEA (0.095 mL, 0.546 mmol) in toluene (1.3 mL), MsCl (0.021 mL, 0.273 mmol) was added at room temperature. After stirring for 1 h, EtOH (0.159 mL, 2.73 mmol) was added. The reaction mixture was allowed to stir at 80° C. for 13 h. To the reaction mixture, additional EtOH (0.79 mL, 13.65 mmol) was added. The mixture was allowed to stir at 80° C. for 4 h. The reaction mixture was cooled to room temperature, and concentrated. The residue was diluted with 2 M aq. Na 2 CO 3 , brine and CH 2 Cl 2 . The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 . The organic layers were combined, dried over Na 2 SO 4 , filtered and concentrated to give title compounds as a mixture, without need of further purification. MS (ESI+) m/z 629.2 (M+H).

(±)-2-((5,7-Dimethyl-1H-indol-4-yl)(ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from a mixture of (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(ethoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(ethoxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile as described in Example 64-B and 64-C. 1 H NMR (TFA salt, 400 MHz, DMSO-d 6 ) δ ppm 10.96 (br.s, 1H) 7.98 (s, 1H) 7.65 (d, J=8.25 Hz, 1H) 7.55 (m, 1H) 7.21 (t, J=2.78 Hz, 1H) 6.74 (s, 1H) 6.56 (dd, J=2.78, 2.02 Hz, 1H) 6.30 (s, 1H) 3.56-3.64 (m, 1H) 3.42-3.50 (m, 1H) 2.42 (s, 3H) 2.41 (s, 3H) 1.22 (t, J=6.95 Hz, 3H). HRMS calcd. for C 21 H 20 N 4 O (M+H) + 345.1710. found 345.1717.

(±)-2-((5,7-Dimethyl-1H-indol-4-yl)(2-methoxyethoxy)methyl)benzo[d]imidazole-5-carbonitrile

The title compound was synthesized as in the Example 73 using 2-methoxyethanol instead of EtOH. 1 H NMR (TFA salt, 400 MHz, DMSO-d 6 ) δ ppm 10.95 (br.s, 1H) 7.97 (s, 1H) 7.64 (d, J=8.34 Hz, 1H) 7.53 (dd, J=8.34, 1.01 Hz, 1H) 7.21 (t, J=2.65 Hz, 1H) 6.74 (s, 1H) 6.57-6.59 (m, 1H) 6.35 (s, 1H) 3.64-3.70 (m, 1H) 3.52-3.57 (m, 3H) 3.24 (s, 3H) 2.43 (s, 3H) 2.41 (s, 3H). HRMS calcd. for C 22 H 22 N 4 O 2 (M+H) + 375.1816. found 375.0894.

2-(5,7-di methyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(5,7-dimethyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

A suspension of a mixture of (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1.89 g, 2.99 mmol), and MnO 2 (1.53 g, 14.94 mmol) in CH 2 Cl 2 (15 mL) was allowed to stir at 40° C. After stirring for 16 hr, additional MnO 2 (1.53 g, 14.94 mmol) was added. The reaction mixture was allowed to stir for further 5 h at the same temperature. The mixture was cooled to room temperature, and then passed through a pad of silica gel (20 g) by eluting with EtOAc (200 mL). The filtrate was concentrated and purified by flash column chromatography on silica gel (heptanes/EtOAc=100:0 to 60:40) to give title compounds as a mixture. MS (ESI+) m/z 599.3 (M+H).

2-(1-(5,7-Dimethyl-1-tosyl-1H-indol-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

To a suspension of methyltriphenylphosphonium bromide (191 mg, 0.534 mmol) in THF (3.56 mL) at 0° C., NaHMDS (1.0M in THF, 0.534 mL, 0.534 mmol) was added. After stirring for 30 minutes, a solution of a mixture of 2-(5,7-dimethyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(5,7-dimethyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (213 mg, 0.356 mmol) in THF (1 mL) was added. The mixture was stirred at 0° C. for 10 minutes and then warmed to room temperature. After 3 days the reaction was quenched with sat. aq. NH 4 Cl and brine, the layers separated and the aqueous layer extracted with EtOAc. The organic extract was dried over MgSO 4 , filtered, and concentrated. The product was purified by flash chromatography (0-100% EtOAc in heptanes) to provide title compounds as a mixture. MS (ESI+) m/z 597.5 (M+H).

(±)-2-(1-(5,7-Dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

To a solution of a mixture of 2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (50 mg, 0.084 mmol) in EtOAc (1 mL) was added Pd/C (5% wet Degussa type, 8.9 mg, 4.19 μmol) and the reaction was stirred at room temperature under hydrogen. After 50 minutes additional Pd/C (5%, 27 mg) was added. After 4 hours total, the reaction was filtered through Celite®, rinsing with EtOAc, and concentrated. The residue was purified by flash chromatography (0-70% EtOAc in heptanes) to provide title compounds as a mixture. MS (ESI+) m/z 599.5 (M+H).

(±)-2-(1-(5,7-Dimethyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from a mixture of (±)-2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile as described in Example 64-B and 64-C. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.22 (br. s., 1H) 10.86 (br. s., 1H) 8.13 (m) 7.69-7.84 (m) 7.36-7.54 (m) 7.05 (t, J=2.78 Hz, 1H) 6.76 (s, 1H) 5.83-5.96 (m, 1H) 4.72-4.90 (m, 1H) 2.39 (s, 3H) 2.37 (s, 3H) 1.76 (d, J=7.07 Hz, 3H). HRMS calcd. for C 20 H 18 N 4 (M+H) + 315.1610. found 315.1610.

(±)-2-(1-(5,7-Dimethyl-1-tosyl-1H-indol-4-yl)-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

To a solution of a mixture of 2-(5,7-dimethyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(5,7-dimethyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 75-A) (1.25 g, 2.09 mmol) in THF (21 mL), 3 M MeMgBr in Et 2 O (1.39 mL, 4.18 mmol) was added at 0° C. After stirring for 1 h, the reaction was quenched with aq. NH 4 Cl and brine. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated to give crude. The crude was purified by flash column chromatography on silica gel (heptanes/EtOAc=100:0 to 45:55) to give title compounds as a mixture. MS (ESI+) m/z 615.4 (M+H).

a) (±)-2-(1-(5,7-Dimethyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from a mixture of (±)-2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile following similar procedures as described in Example 64-B and 64-C. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.30 (br.s, 1H) 10.80 (s, 1H) 8.18 (m) 7.77-7.82 (m) 7.48-7.54 (m) 7.07 (br. s, 1H) 6.63 (s, 1H) 6.23-6.25 (m) 5.96 (s, 1H) 2.38 (s, 3H) 2.11 (s, 3H) 2.07 (s, 3H). HRMS calcd. for C 20 H 18 N 4 O (M+H) + 331.1553. found 331.1559.

b) (+) and (−)-2-(1-(5,7-Dimethyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(1-(5,7-Dimethyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral HPLC using a CHIRALPAK® AS-H column with 20% EtOH (with DEA) in heptane to give (+)-2-(1-(5,7-Dimethyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =7.7 min) and (−)-2-(1-(5,7-Dimethyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =13.2 min).

(±)-2-(1-(5-Ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

A mixture of title compounds was synthesized from a mixture of (±)-2-((5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 70-A) analogously to Example 75-A and 76-A. MS (ESI+) m/z 629.4 (M+H).

(±)-2-(1-(5-Ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of a mixture of (±)-2-(1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1.5 g, 2.38 mmol) and ethylenediamine (1.61 mL, 23.85 mmol) was added TBAF in THF (1M, 23.85 mL, 23.85 mmol), and then the mixture was stirred at 60° C. for 3 h. The reaction was quenched by H 2 O. The layers were separated and the aqueous layer was extracted with EtOAc. The organic phase was successively washed with H 2 O and brine, dried over Na 2 SO 4 , and filtered. After concentration of the filtrate the resulting residue was purified by silica gel flash chromatography (heptanes/EtOAc=66/34, isocratic) to give the title compound. MS (ESI+) m/z 499.3 (M+H).

a) (±)-2-(1-(5-Ethyl-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from (±)-2-(1-(5-Ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile analogously to Example 64-C. 1 H NMR (400 MHz, ACETONITRILE-d 3 with about 5 μL TFA) δ ppm 9.36 (br. s., 1H), 8.12 (s, 1H), 7.82 (d, J=0.76 Hz, 2H), 7.20 (dd, J=3.00, 3.30 Hz, 1H), 6.92 (s, 1H), 6.39 (dd, J=2.02, 3.28 Hz, 1H), 2.50-2.68 (m, 2H), 2.48 (s, 3H), 2.34 (s, 3H), 1.04 (t, J=7.45 Hz, 3H). HRMS calcd. for C 21 H 20 N 4 O (M+H) + 345.1715. found 345.1712.

b) (+) and (−)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a CHIRALPAK® AD-H column with 35% MeOH in CO 2 to give (−)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =2.2 min) and (+)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =3.7 min).

2-(5-Ethyl-7-methyl-1H-indole-4-carbonyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compounds was synthesized as in Example 25A and 25-B from (±)-2-((5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 70-A). 1 H NMR (400 MHz, ACETONITRILE-d 3 with about 5 μL TFA) δ ppm 9.42 (br. s., 1H), 8.12 (dd, J=0.76, 1.39 Hz, 1H), 7.79 (dd, J=0.76, 8.59 Hz, 1H), 7.62 (dd, J=1.50, 8.60 Hz, 1H), 7.22 (dd, J=2.90, 3.03 Hz, 1H), 6.99 (s, 1H), 6.06 (dd, J=2.02, 3.03 Hz, 1H), 2.63 (q, J=7.58 Hz, 2H), 2.55 (d, J=0.88 Hz, 3H), 1.14 (t, J=7.58 Hz, 3H). HRMS calcd. for C 20 H 16 N 4 O (M+H) + 329.1397. found 329.1327.

(±)-2-(1-Hydroxy-1-(5-isopropyl-7-methyl-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-hydroxy-1-(7-methyl-5-propyl-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

A mixture of title compounds was synthesized from a c.a. 5/1 mixture of 5-isopropyl-7-methyl-1-tosyl-1H-indole-4-carbaldehyde and 7-methyl-5-propyl-1-tosyl-1H-indole-4-carbaldehyde (Example 50-A) analogously to the preparation of (±)-2-(1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile (Example 77-B). MS (ESI+) m/z 513.2 (M+H).

a) (±)-2-(1-Hydroxy-1-(5-isopropyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-hydroxy-1-(7-methyl-5-propyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

A mixture of (±)-2-(1-hydroxy-1-(5-isopropyl-7-methyl-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-hydroxy-1-(7-methyl-5-propyl-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (110 mg, 0.215 mmol), isoamylamine (94 mg, 1.073 mmol), and KOH (60.2 mg, 1.073 mmol) was stirred at 100° C. for 0.75 h under the microwave irradiation. The reaction mixture was diluted with CH 2 Cl 2 . The mixture was filtered through SiO 2 . The SiO 2 cake was washed with a mixture of CH 2 Cl 2 /MeOH (c.a. 6/1). Combined organic solution was concentrated and purified by silica gel flash column chromatography (CH 2 Cl 2 /EtOAc=82/18, isocratic) to give (±)-2-(1-hydroxy-1-(5-isopropyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile as a pure isomeric form. 1 H NMR (400 MHz, ACETONITRILE-d 3 with about 5 μL TFA) δ ppm 9.28 (br. s., 1H), 8.05 (s, 1H), 7.73 (d, J=8.60 Hz, 1H), 7.69 (dd, J=1.30, 8.60 Hz, 1H), 7.19 (dd, J=2.80, 2.90 Hz, 1H), 7.00 (s, 1H), 6.66 (dd, J=2.30, 3.00 Hz, 1H), 2.90-3.06 (m, 1H), 2.47 (s, 3H), 2.28 (s, 3H), 0.95 (d, J=6.82 Hz, 3H), 0.92 (d, J=6.57 Hz, 3H). HRMS calcd. for C 22 H 22 N 4 O (M+H) + 359.1867. found 359.1865.

Mixed fractions were concentrated separately and purified by RP-HPLC (HC-A) to give (±)-2-(1-hydroxy-1-(7-methyl-5-propyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile. 1 H NMR (400 MHz, ACETONITRILE-d 3 with about 5 μL TFA) δ ppm 9.37 (br. s., 1H), 8.09-8.19 (m, 1H), 7.76-7.88 (m, 2H), 7.20 (dd, J=3.00, 3.30 Hz, 1H), 6.90 (s, 1H), 6.40 (dd, J=2.02, 3.28 Hz, 1H), 2.42-2.59 (m, 5H), 2.34 (s, 3H), 1.43-1.54 (m, 1H), 1.31-1.42 (m, 1H), 0.74 (t, J=7.33 Hz, 3H). HRMS calcd. for C 22 H 22 N 4 O (M+H) + 359.1867. found 359.1864.

b) (+) and (−)-2-(1-hydroxy-1-(5-isopropyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(1-hydroxy-1-(5-isopropyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a CHIRALPAK® AD-H column with 35% (0.2% diethylamine in MeOH) in CO 2 to give (−)-2-(1-hydroxy-1-(5-isopropyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =1.5 min) and (+)-2-(1-hydroxy-1-(5-isopropyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =2.9 min).

The following compounds were prepared with similar methods.

(±)-2-(1-(5-Ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

To a solution of a mixture of 2-(5-ethyl-7-methyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(5-ethyl-7-methyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 117-A) (1.8 g, 2.94 mmol) and trimethyl(trifluoromethyl)silane (0.918 mL, 5.87 mmol) in THF (20 mL) was added TBAF in THF (1M, 8.81 mL, 8.81 mmol) at room temperature, and then the mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with Et 2 O. The mixture was successively washed by 5% aq. NaHCO 3 , H 2 O and brine, dried over Na 2 SO 4 , and filtered. Concentration of the filtrate gave title compounds as a mixture without need of further purification. MS (ESI+) m/z 683.5 (M+H).

(±)-2-(1-(5-Ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile

A mixture of (±)-2-(1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1.16 g, 1.69 mmol) and HCl in MeOH (1.25 M, 13.59 mL, 16.99 mmol) was allowed to stir at 60° C. for 0.5 h. The reaction mixture was cooled to rt and concentrated. The residue was dissolved in a small amount of EtOAc, and then diluted with heptanes. The precipitated solid was collected on a Kiriyama funnel, washed with hexane, dried under reduced pressure to give the title compound. MS (ESI+) m/z 553.3 (M+H).

a) (±)-2-(1-(5-Ethyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of a mixture of 2-(5-ethyl-7-methyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(5-ethyl-7-methyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (400 mg, 0.653 mmol) and trimethyl(trifluoromethyl)silane (0.204 mL, 1.30 mmol) in THF (1 mL) was added dropwise TBAF in THF (1M, 1.95 mL, 1.95 mmol) at 0° C., and then the mixture was stirred at room temperature for 0.5 hr. To the mixture were added ethylenediamine (0.441 mL, 6.53 mmol) and TBAF in THF (1M, 6.53 mL, 6.53 mmol), and then the mixture was stirred at 60° C. for 77 h. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with EtOAc and successively washed by 5% aq. NaHCO 3 , H 2 O and brine, dried over Na 2 SO 4 , and filtered. After concentration the residue was purified by silica gel flash chromatography [heptanes/(30% EtOAc in CH 2 Cl 2 )=44/55] to give the title compound. 1 H NMR (400 MHz, ACETONITRILE-d 3 with about 5 μL TFA) δ ppm 9.25 (br. s., 1H), 8.10 (s, 1H), 7.67 (d, J=8.30 Hz, 1H), 7.61 (dd, J=1.30, 8.30 Hz, 1H), 7.04 (t, J=3.00 Hz, 1H), 6.97 (s, 1H), 6.02 (br. s., 1H), 5.32 (br. s., 1H), 2.92-3.04 (m, 1H), 2.51-2.59 (m, 1H), 2.50 (d, J=0.76 Hz, 3H), 1.12 (t, J=7.33 Hz, 3H). HRMS calcd. for C 21 H 17 F 3 N 4 O (M+H) + 399.1427. found 399.1420.

b) (+) and (−)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a CHIRALPAK® AD-H column with 15% MeOH in CO 2 to give (−)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =3.2 min) and (+)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =6.9 min).

The following compounds were prepared with similar methods.

2-(5-Bromo-7-methyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(5-bromo-7-methyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

A mixture of title compounds was prepared from 5-bromo-7-methyl-1-tosyl-1H-indole-4-carbaldehyde (Example 55-C) analogously to the preparation of title compound in Example 75-A. MS (ESI+) m/z 663.3, 665.3 (M+H).

Methyl 4-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-7-methyl-1-tosyl-1H-indole-5-carboxylate and methyl 4-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-7-methyl-1-tosyl-1H-indole-5-carboxylate

A septum-sealed flask containing a mixture of 2-(5-bromo-7-methyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethyl-silyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(5-bromo-7-methyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethyl-silyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (1 g, 1.5 mmol), palladium acetate (0.034 g, 0.151 mmol), and Xantphos (0.174 g, 0.301 mmol) was evacuated and filled with CO gas and placed under CO atmosphere (balloon). Toluene (12 mL), methanol (3.05 mL, 75 mmol) and triethylamine (0.63 mL, 4.52 mmol) were then added to the reaction mixture. The reaction mixture was stirred at room temperature for 5 min and then stirred at 75° C. until the starting material had been completely consumed. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate. The reaction mixture was filtered through a plug of Celite®, washed with ethyl acetate and concentrated under reduced pressure. The residue was purified via silica gel flash column chromatography (0 to 80% (30% EtOAc in CH 2 Cl 2 )-heptanes) to give a mixture of title compounds. MS (ESI+) m/z 643.6 (M+H).

(±)-2-(5-Methyl-3-oxo-1-(trifluoromethyl)-3,6-dihydro-1H-furo[3,4-e]indol-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(5-methyl-3-oxo-1-(trifluoromethyl)-3,6-dihydro-1H-furo[3,4-e]indol-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

To a solution of a mixture of methyl 4-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-7-methyl-1-tosyl-1H-indole-5-carboxylate and methyl 4-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-7-methyl-1-tosyl-1H-indole-5-carboxylate (460 mg, 0.69 mmol) and trimethyl(trifluoromethyl)silane (0.22 mL, 1.39 mmol) in THF (7 mL) at 0° C., TBAF (1M in THF, 2.08 mL, 2.08 mmol) was added slowly. After addition, the reaction was stirred at 0° C. for 10 min, then warmed to room temperature for 20 min. The reaction was quenched with a sat. aq. NaHCO 3 solution, the layers were separated and the aqueous layer extracted with ethyl acetate and dried over Na 2 SO 4 . After concentration under reduced pressure, the residue was purified via silica gel flash column chromatography (heptane/(30% EtOAc in CH 2 Cl 2 )=0 to 60%) to give title compounds as a mixture. MS (ESI+) m/z 527.5 (M+H).

(±)-2-(5-Methyl-3-oxo-1-(trifluoromethyl)-3,6-dihydro-1H-furo[3,4-e]indol-1-yl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of a mixture of (±)-2-(5-methyl-3-oxo-1-(trifluoromethyl)-3,6-dihydro-1H-furo[3,4-e]indol-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(5-methyl-3-oxo-1-(trifluoromethyl)-3,6-dihydro-1H-furo[3,4-e]indol-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (36 mg, 0.068 mmol) in THF (0.5 mL), TBAF (1M in THF, 1.37 mL, 1.37 mmol) was added. The reaction was stirred at 75° C. for 30 min. The reaction mixture was cooled to room temperature, diluted with brine, and the layers were separated. The aqueous layer was extracted with ethyl acetate and dried over Na 2 SO 4 . After concentration, the residue was purified via silica gel flash chromatography (heptanes/((30% EtOAc in CH 2 Cl 2 )=0 to 100%) to give the title compound. 1 H NMR (400 MHz, ACETONITRILE-d 3 ) δ ppm 10.09 (br. s., 1H), 8.06 (s, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.58 (dd, J=8.5, 1.5 Hz, 1H), 7.54-7.57 (m, 1H), 7.53 (d, J=0.8 Hz, 1H), 7.00-7.04 (m, 1H), 2.63 (d, J=0.8 Hz, 3H). HRMS calcd. for C 20 H 11 F 3 N 4 O 2 (M+H) + 397.0907. found 397.0902.

(±)-2-(2,2,2-Trifluoro-1-hydroxy-1-(5-(hydroxymethyl)-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of (±)-2-(5-methyl-3-oxo-1-(trifluoromethyl)-3,6-dihydro-1H-furo[3,4-e]indol-1-yl)-1H-benzo[d]imidazole-5-carbonitrile (47 mg, 0.119 mmol) in THF (0.5 mL) at 0° C., LiBH 4 (2N in THF, 1.19 mL, 2.38 mmol) was added, followed by H 2 O (43 μL, 2.38 mmol). The reaction was stirred at 50° C. for 16 hours and then cooled to 0° C. A NH 4 Cl aqueous solution was added and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na 2 SO 4 . After concentration under reduced pressure, the residue was separated via silica gel flash column chromatography (CH 2 Cl 2 /EtOAc=0 to 100%) to give the title compound. 1 H NMR (400 MHz, ACETONITRILE-d 3 with about 3% METHANOL-d 4 ) δ ppm 8.05 (s, 1H), 7.54-7.70 (m, 2H), 7.13 (s, 1H), 6.97 (d, J=3.2 Hz, 1H), 5.54 (br. s., 1H), 5.20 (d, J=12.8 Hz, 1H), 4.68 (d, J=12.0 Hz, 1H), 2.48 (s, 3H). HRMS calcd. for C 20 H 16 F 3 N 4 O 2 (M+H) + 401.122. found 401.1214.

(±)-4-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-N,7-dimethyl-1H-indole-5-carboxamide

To a suspension of methylamine hydrochloride (102 mg, 1.51 mmol) in THF (0.5 mL), 2N isopropylmagnesium chloride in THF (1.51 mL, 3.03 mmol) was added. The reaction was stirred at room temperature for 3 hr, then a solution of (±)-2-(5-methyl-3-oxo-1-(trifluoromethyl)-3,6-dihydro-1H-furo[3,4-e]indol-1-yl)-1H-benzo[d]imidazole-5-carbonitrile (30 mg, 0.076 mmol) in THF (0.5 mL) was added. The reaction was allowed to stir at room temperature for 16 hours. The reaction mixture was quenched with 1N HCl aqueous solution and then neutralized by adding NaHCO 3 . The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over Na 2 SO 4 . After concentration under reduced pressure, the residue was separated via silica gel flash column chromatography (CH 2 Cl 2 /EtOAc=0 to 100%) to give the title compound. 1 H NMR (400 MHz, DMSO-d 6 , with about 3% METHANOL-d 4 ) δ ppm 7.85 (d, J=2.0 Hz, 1H), 7.41-7.46 (m, 2H), 7.39 (d, J=0.8 Hz, 1H), 7.19 (dd, J=8.3, 1.8 Hz, 1H), 6.50 (d, J=2.5 Hz, 1H), 2.96 (s, 3H), 2.58 (s, 3H). HRMS calcd. for C 21 H 16 F 3 N 5 O 2 (M+H) + 428.1329. found 428.1333.

2-(7-Methyl-1-tosyl-5-(trifluoromethyl)-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(7-methyl-1-tosyl-5-(trifluoromethyl)-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

To methyl 2-(fluorosulfonyl)difluoroacetate (129 uL, 0.979 mmol), a mixture of 2-(5-bromo-7-methyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and 2-(5-bromo-7-methyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (Example 81-A) (260 mg, 0.392 mmol) in DMF (3.9 mL) was added CuI (8.95 mg, 0.047 mmol). The reaction mixture was stirred at 80° C. for 3 hours under microwave irradiation. After cooling the reaction was diluted with water, the layers separated and the aqueous layer was extracted with 80% EtOAc in Heptane. The organic phase was washed with water and concentrated. The residue was purified with Heptane-(30% EtOAc in DCM) to provide a mixture of title compounds. MS (ESI+) m/z 653.2 (M+H).

(±)-2-(1-hydroxy-1-(7-methyl-5-(trifluoromethyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from a mixture of 2-(7-methyl-1-tosyl-5-(trifluoromethyl)-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(7-methyl-1-tosyl-5-(trifluoromethyl)-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile using the same procedures as described in Example 64-B and 64-C. 1 H NMR (400 MHz, DICHLOROMETHANE-d 2 with 5% of METHANOL-d 4 ) δ ppm 9.24 (br. s., 1H) 7.92 (s, 1H) 7.57-7.65 (m, 1H) 7.51-7.55 (m, 1H) 7.47 (s, 1H) 6.99-7.12 (m, 1H) 5.96 (dd, J=3.41, 1.89 Hz, 1H) 2.53 (s, 3H) 2.34 (s, 3H). HRMS calcd. for C 20 H 15 F 3 N 4 O (M+H) + 385.1271. found 385.1277.

(±)-2-(1-(5,7-Dimethyl-1-tosyl-1H-indol-4-yl)-1-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)-1-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

A mixture of title compounds was synthesized by alkylation of a mixture of (±)-2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)-1-hydroxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 76-A) analogously to Example 25-A. MS (ESI+) m/z 629.2 (M+H).

a) (±)-2-(1-(5,7-Dimethyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from a mixture of (±)-2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)-1-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)-1-methoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile analogously to Example 64-B and 64-C. 1 H NMR (TFA salt, 400 MHz, DMSO-d 6 ) δ ppm 10.89 (s, 1H) 8.07 (s, 1H) 7.55-7.64 (m, 2H) 7.12 (t, J=2.78 Hz, 1H) 6.67 (s, 1H) 6.08 (dd, J=3.03, 2.02 Hz, 1H) 3.05 (s, 3H) 2.39 (s, 3H) 2.05 (s, 3H) 2.03 (s, 3H). HRMS calcd. for C 21 H 20 N 4 O (M+H) + 345.1710. found 345.1715.

b) (+) and (−)-2-(1-(5,7-dimethyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(1-(5,7-dimethyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by normal phase chiral HPLC using a CHIRALPAK® IC column with 30% EtOH in heptane to give (−)-2-(1-(5,7-dimethyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =5.5 min) and (+)-2-(1-(5,7-dimethyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =8.3 min).

The following compounds were prepared with similar methods.

2-((3-bromo-5,7-dimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

2-((5,7-Dimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (Example 58-C) (61 mg, 0.203 mmol) was dissolved in DMF (2 mL) and NBS (40.1 mg, 0.225 mmol) was added at 0° C. and the reaction stirred for 1 hour. The reaction was then quenched with saturated aq. sodium thiosulfate and saturated aq. NaHCO 3 . The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic phase was dried over MgSO 4 , concentrated and purified by flash column chromatography (0-40% EtOAc in heptanes) to provide the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.33 (br. s., 1H) 11.39 (br. s., 1H) 7.97 (s, 1H) 7.83 (s, 1H) 7.41-7.64 (m, 2H) 6.86 (s, 1H) 4.82 (d, J=4.55 Hz, 2H) 2.43 (s, 3H) 2.21 (s, 3H). HRMS calcd. for C 19 H 15 BrN 4 (M+H) + 379.0553. found 379.0557.

2-((3-Chloro-5,7-dimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized by a chlorination of 2-((5,7-dimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile using NCS analogously to the preparation of Example 85. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.38 (s, 1H) 11.29 (br. s., 1H) 7.98 (d, J=0.76 Hz, 1H) 7.75-7.87 (m, 1H) 7.61 (d, J=8.34 Hz, 1H) 7.44-7.55 (m) 7.39-7.44 (m) 6.86 (s, 1H) 4.75 (d, J=4.55 Hz, 2H) 2.42 (s, 3H) 2.24 (s, 3H). HRMS calcd. for C 13 H 16 ClN 4 (M+H) + 335.1058. found 335.1062.

(±)-2-((3-Chloro-5-ethyl-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from (±)-2-((5-ethyl-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (Example 67-A) as described in Example 86. 1 H NMR (400 MHz, DICHLOROMETHANE-d 2 with about 5 μL TFA) δ ppm 8.47 (br. s., 1H), 8.01 (s, 1H), 7.81 (d, J=8.60 Hz, 1H), 7.76 (br. d, J=8.60 Hz, 1H), 7.32 (br. s., 1H), 7.25 (s, 1H), 7.05 (s, 1H), 2.62-2.82 (m, 2H), 2.51 (s, 3H), 1.18 (t, J=7.45 Hz, 3H). HRMS calcd. for C 20 H 17 ClN 4 O (M+H) + 365.1164. found 365.1167.

(+)-2-(1-(5-Ethyl-7-methyl-3-(trifluoromethyl)-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile

To a suspension of (+)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile (Example 77-C) (20 mg, 0.058 mmol) and K 2 CO 3 (56.2 mg, 0.406 mmol) in DMF (0.5 mL) was added 5-(trifluoromethyl)-5H-dibenzo[b,d]thiophenium trifluoromethanesulfonate (117 mg, 0.290 mmol), and then the mixture was stirred at 70° C. for 2 h. The reaction was quenched by 5% aq. NaHCO 3 . The layers were separated and the aqueous layer was extracted with EtOAc. The organic layer was washed with H 2 O and brine, dried over Na 2 SO 4 , and filtered. After concentration, the residue was purified by silica gel column chromatography (CH 2 Cl 2 /EtOAc=94/6 to 51/49) to give the title compound. 1 H NMR (400 MHz, ACETONITRILE-d 3 with about 5 μL TFA) δ ppm 9.86 (br. s., 1H), 8.00 (dd, J=0.68, 1.44 Hz, 1H), 7.66 (dd, J=0.68, 8.50 Hz, 1H), 7.62 (dd, J=1.44, 8.50 Hz, 1H), 7.21-7.25 (m, 1H), 7.02 (s, 1H), 2.48 (d, J=0.76 Hz, 3H), 2.41 (q, J=7.45 Hz, 2H), 2.22 (s, 3H), 0.91 (t, J=7.45 Hz, 3H). HRMS calcd. for C 22 H 19 F 3 N 4 O (M+H) + 413.1584. found 413.1588.

2-(5,7-Dimethyl-1H-indole-4-carbonyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from a mixture of 2-(5,7-dimethyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(5,7-dimethyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 75-A) analogously to Example 64-B and 64-C. MS (ESI+) m/z 315.1 (M+H).

2-(3-Formyl-5,7-dimethyl-1H-indole-4-carbonyl)-1H-benzo[d]imidazole-5-carbonitrile

To a suspension of 2-(5,7-dimethyl-1H-indole-4-carbonyl)-1H-benzo[d]imidazole-5-carbonitrile (79 mg, 0.251 mmol) in CH 2 Cl 2 (20 mL) was added N-(chloromethylene)-N-methylmethanaminium chloride (48.3 mg, 0.377 mmol) at room temperature, and then the mixture was stirred at room temperature for 2.5 h. To the mixture was added N-(chloromethylene)-N-methylmethanaminium chloride (32.2 mg, 0.251 mmol), and then the mixture was stirred at room temperature for another 6 h. The reaction was quenched by 5M aq. HCl (2 mL), followed by MeOH. The mixture was stirred at room temperature for 17 h. The mixture was basified by 5% aq. NaHCO 3 , the layers were separated and the aqueous layer was extracted with CH 2 Cl 2 /2,2,2-trifluoroethanol (c.a. 9/1). The organic phase was washed with H 2 O and brine, dried over Na 2 SO 4 , and filtered. Concentration of the filtrate gave crude, which was purified by silica gel flash column chromatography (CH 2 Cl 2 /EtOAc=1/0 to 54/46 then hold) to give the title compound. MS (ESI+) m/z 343.1 (M+H).

2-(3,5,7-Trimethyl-1H-indole-4-carbonyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of 2-(3-formyl-5,7-dimethyl-1H-indole-4-carbonyl)-1H-benzo[d]imidazole-5-carbonitrile (20 mg, 0.058 mmol) in MeOH (2 mL) was added NaBH 4 (11.05 mg, 0.292 mmol), and then the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with EtOAc/2,2,2-trifluoroethanol (c.a. 9/1). The organic phase was successively washed by H 2 O and brine, dried over Na 2 SO 4 , and filtered. Concentration of the filtrate gave the title compound, which was used in the next reaction without any further purification. MS (ESI+) m/z 329.1 (M+H).

(±)-2-(Hydroxy(3,5,7-trimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

A solution of 2-(3,5,7-trimethyl-1H-indole-4-carbonyl)-1H-benzo[d]imidazole-5-carbonitrile (20 mg, 0.061 mmol) and LiBH 4 in THF (2M, 2 mL, 4.00 mmol) was stirred at 50° C. for 2 h. The reaction mixture was cooled to room temperature. The mixture was quenched by half satd. aq. KHSO 4 and basified by 5% NaHCO 3 . The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 /2,2,2-trifluoroethanol (c.a. 9/1). The organic phase was washed with H 2 O and brine, dried over Na 2 SO 4 , and filtered. After concentration of the filtrate the resulting residue was purified by RP-HPLC (HC-A) to give the title compound. 1 H NMR (400 MHz, ACETONITRILE-d 3 with about 5 μL TFA) δ ppm 9.10 (br. s., 1H), 8.08 (s, 1H), 7.73-7.82 (m, 2H), 7.06 (s, 1H), 6.96 (s, 1H), 6.84 (s, 1H), 2.45 (s, 3H), 2.21 (br. s., 3H), 2.19 (s, 3H). HRMS calcd. for C 20 H 18 N 4 O (M+H) + 331.1554. found 331.1555.

2-((3-Cyano-5-ethyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

To a suspension of 2-((5-ethyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (15 mg, 0.048 mmol) in DMF (1 mL) was added chlorosulfonyl isocyanate (17 μL, 0.191 mmol) at 0° C., and then the mixture was stirred at 0° C. for 1.5 h. The mixture was allowed to warm up to room temperature with stirring. After 13.5 h, the reaction was quenched by 28% aq. NH 4 OH. The mixture was stirred for 0.25 h and then extracted with EtOAc/2,2,2-trifluoroethanol (c.a. 9/1). The organic layer was washed with H 2 O and brine, dried over Na 2 SO 4 , and filtered. After concentration, the resulting residue was purified by silica gel flash column chromatography [CH 2 Cl 2 /(2M NH 3 in MeOH)=98/2, isocratic] to give the title compound. 1 H NMR (400 MHz, ACETONITRILE-d 3 with about 5 μL TFA) δ ppm 10.22 (br. s., 1H), 8.07 (dd, J=1.00, 1.10 Hz, 1H), 7.91 (d, J=3.16 Hz, 1H), 7.71-7.85 (m, 2H), 7.15 (s, 1H), 5.02 (s, 2H), 2.71 (q, J=7.60 Hz, 2H), 2.54 (d, J=0.63 Hz, 3H), 1.14 (t, J=7.58 Hz, 3H). HRMS calcd. for C 21 H 17 N 5 (M+H) + 340.1557. found 340.1556.

(−)-2-((3-Cyano-5-ethyl-7-methyl-1H-indol-4-yl)(methoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from (−)-2-((5-ethyl-7-methyl-1H-indol-4-yl)(methoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile as described in Example 90. 1 H NMR (400 MHz, ACETONITRILE-d 3 with about 5 μL TFA) δ ppm 10.12 (br. s., 1H), 7.93 (s, 1H), 7.80 (d, J=3.28 Hz, 1H), 7.65 (dd, J=0.60, 8.60 Hz, 1H), 7.60 (dd, J=1.50, 8.60 Hz, 1H), 7.03 (s, 1H), 6.46 (s, 1H), 3.36 (s, 3H), 2.58-2.71 (m, 2H), 2.44 (d, J=0.76 Hz, 3H), 1.01 (t, J=7.58 Hz, 3H). HRMS calcd. for C 22 H 19 N 5 O (M+H) + 370.1663. found 370.1661.

2-((5-Ethyl-7-methyl-3-(2,2,2-trifluoroacetyl)-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

To a suspension of 2-((5-ethyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (200 mg, 0.382 mmol) in CH 2 Cl 2 (10 mL) was added trifluoroacetic anhydride (162 μL, 1.145 mmol), and then the mixture was stirred at room temperature for 0.75 hr. The reaction mixture was cooled to 0° C. The solid that was generated was collected by filtration to give the title compound, without need of further purification. MS (ESI+) m/z 411.3 (M+H).

(±)-2-((5-Ethyl-7-methyl-3-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of 2-((5-ethyl-7-methyl-3-(2,2,2-trifluoroacetyl)-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (60 mg, 0.114 mmol) in MeOH (10 mL) was added portionwise NaBH 4 (21.6 mg, 0.572 mmol). The mixture was stirred at room temperature for 3 h, and then for 16 h at 60° C. The reaction mixture was diluted with H 2 O. The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 . The combined organic phase was washed with H 2 O and brine, dried over Na 2 SO 4 , filtered and concentrated. The resulting residue was purified by silica gel flash column chromatography [CH 2 Cl 2 /(2M NH 3 in MeOH)=94/6, isocratic] to give the title compound. 1 H NMR (400 MHz, ACETONITRILE-d 3 with about 5 μL TFA) δ ppm 9.50 (br. s., 1H), 7.83 (s, 1H), 7.54 (d, J=8.30 Hz, 1H), 7.47 (d, J=8.30 Hz, 1H), 7.42 (br. s., 1H), 6.95 (s, 1H), 5.56 (q, J=7.28 Hz, 1H), 4.78 (d, J=17.40 Hz, 1H), 4.64 (d, J=17.43 Hz, 1H), 2.74 (q, J=7.45 Hz, 2H), 2.45 (s, 3H), 1.12 (t, J=7.52 Hz, 3H). HRMS calcd. for C 22 H 19 F 3 N 4 O (M+H) + 413.1584. found 413.1583.

1-(5,7-Dimethyl-1-tosyl-1H-indol-4-yl)prop-2-en-1-one

To a solution of 5,7-dimethyl-1-tosyl-1H-indole-4-carbaldehyde (Example 46-D) (500 mg, 1.53 mmol) in THF (15 mL) at −78° C., vinylmagnesium bromide (2.29 mL, 2.29 mmol) was added and the reaction was stirred for 15 minutes. At this point a saturated water solution of NH 4 Cl was added. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were dried over MgSO 4 and evaporated. The resulting residue was dissolved in DCM (4 mL), and Dess-Martin Periodinane (1.19 g, 2.81 mmol) was added. After 15 minutes the reaction was complete. The reaction was quenched with a sat. aq. solution of NaHCO 3 and sodium thiosulfate. The layers were separated and the aqueous layer was extracted with DCM. It was purified using FCC eluting with heptane/EtOAc 1:1 to give the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.85 (d, J=3.79 Hz, 1H), 7.50-7.66 (m, J=8.34 Hz, 2H), 7.30-7.45 (m, J=8.34 Hz, 2H), 7.01 (s, 1H), 6.71 (dd, J=10.48, 17.56 Hz, 1H), 6.59 (d, J=4.04 Hz, 1H), 6.14 (d, J=10.86 Hz, 1H), 5.88 (d, J=17.43 Hz, 1H), 2.35 (s, 3H), 2.21 (s, 3H).

6,8-Dimethyl-1-tosylbenzo[cd]indol-5(1H)-one

To a mixture of 1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)prop-2-en-1-one (240 mg, 0.679 mmol), PdOAc 2 (152 mg, 0.679 mmol) and P-CHLORANIL (167 mg, 0.679 mmol), AcOH (7 mL) was added and the reaction heated to 100° C. for 1.5 h. The reaction was stopped and filtered to remove precipitated salts. The AcOH was removed in vacuo and then the resulting residue was purified using FCC eluting with heptane:EtOAc 1:1 to give the title compound. MS (ESI+) m/z 352.3 (M+H).

(±)-2-(5-hydroxy-6,8-dimethyl-1-tosyl-1,5-dihydrobenzo[cd]indol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and (±)-2-(5-hydroxy-6,8-dimethyl-1-tosyl-1,5-dihydrobenzo[cd]indol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

To a solution of a mixture of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (467 mg, 1.707 mmol) in THF (9 mL), LDA (0.785 mL, 1.571 mmol) was added and the reaction left stirring at −78° C. for 30 minutes. 6,8-Dimethyl-1-tosylbenzo[cd]indol-5(1H)-one (240 mg, 0.683 mmol) in THF was added and the reaction allowed to stir for 1 h at −78° C. The reaction was quenched with a saturated aq. solution of ammonium chloride, extracted with EtOAc and evaporated to give the crude product. The resulting residue was purified using heptane/EtOAc 1:1 to give the mixture of title compounds. MS (ESI+) m/z 625.5 (M+H).

(±)-2-(5-Hydroxy-6,8-dimethyl-1-tosyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and (±)-2-(5-hydroxy-6,8-dimethyl-1-tosyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile

A solution of a mixture of (±)-2-(5-hydroxy-6,8-dimethyl-1-tosyl-1,5-dihydrobenzo[cd]indol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and (±)-2-(5-hydroxy-6,8-dimethyl-1-tosyl-1,5-dihydrobenzo[cd]indol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (50 mg, 0.080 mmol) in MeOH was charged with Pd/C (10%, 5 mg). The atmosphere was changed from N 2 to H 2 (balloon) and stirred for 2 h, at this point more Pd/C (10%, 5 mg) was added and the reaction was complete after 2 more hours. The mixture was filtered and evaporated to give the mixture of title compounds. MS (ESI+) m/z 628.5 (M+2H).

(±)-2-(5-Hydroxy-6,8-dimethyl-1-tosyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1H-benzo[d]imidazole-5-carbonitrile

To a mixture of (±)-2-(5-hydroxy-6,8-dimethyl-1-tosyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and (±)-2-(5-hydroxy-6,8-dimethyl-1-tosyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (50 mg, 0.08 mmol), lithium tetrafluoroborate (1.5 mL, 1.5 mmol) and H 2 O (0.15 mL) were added. The reaction was heated to 70° C. overnight. It was quenched with a sat. NaHCO 3 solution. The layers were separated and the aqueous layer was extracted with EtOAc. It was purified using FCC eluting with heptane:EtOAc 1:2 to give the title compound. MS (ESI+) m/z 497.4 (M+H).

a) (±)-2-(5-Hydroxy-6,8-dimethyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1H-benzo[d]imidazole-5-carbonitrile

(±)-2-(5-Hydroxy-6,8-dimethyl-1-tosyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1H-benzo[d]imidazole-5-carbonitrile (41 mg, 0.083 mmol) in EtOH (0.83 mL) was treated with isomylamine (190 μL, 1.65 mmol) and KOH (46.3 mg, 0.826 mmol) and heated in a microwave for 30 minutes at 100° C. After 30 minutes an additional aliquot of isomylamine (190 μL, 1.65 mmol) and KOH (46.3 mg, 0.826 mmol) were added and the reaction heated in a microwave. After 30 minutes the reaction was complete. It was directly loaded onto a column and purified using FCC eluting with heptane:EtOAc 1:2 to give the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.79 (s, 1H), 10.59 (br. s., 1H), 7.89-7.95 (m, 1H), 7.55-7.72 (m, 1H), 7.34-7.55 (m, 1H), 7.01 (s, 1H), 6.56 (s, 1H), 6.15 (m, 1H), 2.89-2.90 (m, 2H), 2.27-2.45 (m, 5H). HRMS calcd. for C 21 H 18 N 4 O (M+H) + 343.1554. found 343.156.

b) (+) and (−)-2-(5-hydroxy-6,8-dimethyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(5-hydroxy-6,8-dimethyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a CHIRALPAK® AD-H column with 35% (0.2% diethylamine in MeOH) in CO 2 to give (+) or (−)-2-(5-hydroxy-6,8-dimethyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1H-benzo[d]imidazole-5-carbonitrile (t r =7.2 min) and (−) or (+)-2-(5-hydroxy-6,8-dimethyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1H-benzo[d]imidazole-5-carbonitrile (t r =10.2 min).

a) (±)-2-(6-ethyl-5-hydroxy-8-methyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized starting from 5-ethyl-7-methyl-1-tosyl-1H-indole-4-carbaldehyde following same procedures as described in Example 93. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.78 (s, 1H), 10.59 (s, 1H), 7.87-7.93 (m, 1H), 7.54-7.65 (m, 1H), 7.42-7.54 (m, 1H), 7.01 (s, 1H), 6.63 (s, 1H), 6.11-6.24 (m, 1H), 2.87 (m, 2H), 2.41 (s, 3H), 2.21-2.38 (m, 4H), 0.72-0.89 (m, 3H). HRMS calcd. for C 22 H 20 N 4 O (M+H) + 357.171. found 357.1718.

b) (+) and (−)-2-(6-ethyl-5-hydroxy-8-methyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(6-ethyl-5-hydroxy-8-methyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a CHIRALCEL® OD-H column with 25% (0.2% diethylamine in MeOH) in CO 2 to give (+) or (−)-2-(6-ethyl-5-hydroxy-8-methyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1H-benzo[d]imidazole-5-carbonitrile (t r =4.5 min) and (−) or (+)-2-(6-ethyl-5-hydroxy-8-methyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1H-benzo[d]imidazole-5-carbonitrile (t r =6.3 min).

(±)-N-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)-2,2,2-trifluoroacetamide and (±)-N-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)-2,2,2-trifluoroacetamide

A solution of a mixture of (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 64-A) (240 mg, 0.399 mmol), DBU (0.18 mL, 1.198 mmol), and DPPA (0.26 mL, 1.19 mmol) in toluene (4 mL) was allowed to stir at rt for 16 h. The reaction mixture was diluted with 2M aq. Na 2 CO 3 and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic phase was washed with 1M aq. KHSO 4 and brine, dried over Na 2 SO 4 , filtered, and concentrated.

A resulting residue was dissolved in EtOH (8 mL) and hydrogenated using H-Cube® apparatus (1 atm, rt, 10% Pd/C, 1 mL/min.) until the reaction completed. The reaction mixture was concentrated and the resulting residue was dissolved in CH 2 Cl 2 (4 mL), and DIPEA (0.14 mL, 0.8 mmol) and (CF 3 CO) 2 O (0.084 mL, 0.599 mmol) were added at rt. After stirring for 5 min, the reaction mixture was diluted with brine and CH 2 Cl 2 . The layers were separated and the organic layer was dried over MgSO 4 , filtered and evaporated. The residue was purified by flash column chromatography on silica gel (heptanes/EtOAc=100:0 to 55:45) to give the mixture of title compounds. MS (ESI+) m/z 696.28 (M+H).

a) (±)-2-(Amino(5,7-dimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from a mixture of (±)-N-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)-2,2,2-trifluoroacetamide and (±)-N-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)-2,2,2-trifluoroacetamide as described in Example 64-B and 64-C. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.88 (s, 1H) 7.93 (s, 1H) 7.59 (d, J=8.08 Hz, 1H) 7.48 (app dd, J=8.34, 1.26 Hz, 1H) 7.11 (t, J=2.78 Hz, 1H) 6.73 (s, 1H) 6.19 (s, 1H) 5.77 (s, 1H) 2.43 (s, 3H) 2.39 (s, 3H). HRMS calcd. for C 19 H 17 N 5 (M+H) + 316.1557. found 316.1563.

b) (+) and (−)-2-(amino(5,7-dimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(amino(5,7-dimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a CHIRALCEL® OD-H column with 50% i-PrOH (with 0.2% DEA) in CO 2 to give (+)-2-(amino(5,7-dimethyl-1H-indol-4-yl)methyl)benzo[d]imidazole-5-carbonitrile (t r =0.6 min) and (−)-2-(amino(5,7-dimethyl-1H-indol-4-yl)methyl)benzo[d]imidazole-5-carbonitrile (t r =1.2 min).

(±)-N-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)methyl)-2-methylpropane-2-sulfinamide and (±)-N-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)methyl)-2-methylpropane-2-sulfinamide

A suspension of a mixture of 2-(5-ethyl-7-methyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(5-ethyl-7-methyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 117-A) (500 mg, 0.816 mmol), and (±)-2-methylpropane-2-sulfinamide (129 mg, 1.061 mmol) in Ti(O-iPr) 4 (1.43 mL, 4.90 mmol) was stirred at 90° C. for 5 h. The reaction mixture was cooled down to 0° C., and then diluted with MeOH (30 mL). To the mixture was added portionwise NaBH 4 (617 mg, 16.32 mmol) at 0° C., and then the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with CH 2 Cl 2 . Celite® was added to the mixture, and then the mixture was diluted with H 2 O with stirring. The mixture was filtered. The Celite® cake was washed with CH 2 Cl 2 . The combined organic phase was washed successively by H 2 O and brine, dried over Na 2 SO 4 , and filtered. Concentration of the filtrate gave the title compounds as a mixture, without need of further purification. MS (ESI+) m/z 718.6 (M+H).

(±)-2-(Amino(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

A solution of a mixture of (±)-N-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)methyl)-2-methylpropane-2-sulfinamide and (±)-N-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)methyl)-2-methylpropane-2-sulfinamide (574 mg, 0.8 mmol) in 1M HCl in MeOH (10 mL) was stirred at room temperature for 1.5 h, and then at 60° C. for 18 h. The reaction mixture was basified by 5% aq. NaHCO 3 . The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 . The organic phase was successively washed with H 2 O and brine, dried over Na 2 SO 4 , and filtered. After concentration the residue was purified by silica gel flash column chromatography (heptanes/EtOAc=1/1 to 0/1) to give the title compound. MS (ESI+) m/z 484.2 (M+H).

a) (±)-2-(Amino(5-ethyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from (±)-2-(amino(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile as described in Example 64-C. 1 H NMR (400 MHz, ACETONITRILE-d 3 with about 5 μL TFA) δ ppm 9.50 (br. s., 1H), 8.00 (s, 1H), 7.56-7.60 (m, 1H), 7.12 (t, J=3.00 Hz, 1H), 7.02 (s, 1H), 6.42 (s, 1H), 5.75-5.83 (m, 1H), 2.92-3.02 (m, 1H), 2.81-2.91 (m, 1H), 2.51 (d, J=0.76 Hz, 3H), 1.29 (t, J=7.58 Hz, 3H). HRMS calcd. for C 20 H 19 N 5 (M+H) + 330.1713. found 330.1707.

b) (+) and (−)-2-(Amino(5-ethyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(amino(5-ethyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by normal phase chiral HPLC using a CHIRALCEL® OD column with 0.2% diethylamine in EtOH to give (+)-2-(amino(5-ethyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =6.6 min) and (−)-2-(amino(5-ethyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =9.4 min).

a) (±)-2-(Amino(5-isopropyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized following the same procedures that led to 2-(amino(5-ethyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (Example 96) starting from 5-Isopropyl-7-methyl-1-tosyl-1H-indole-4-carbaldehyde (Example 50-A). 1 H NMR (400 MHz, ACETONITRILE-d 3 with about 5 μL TFA) δ ppm 9.50 (br. s., 1H), 8.00 (s, 1H), 7.60 (d, J=8.30 Hz, 1H), 7.56 (dd, J=1.50, 8.30 Hz, 1H), 7.05-7.20 (m, 2H), 6.55 (s, 1H), 5.71-5.88 (m, 1H), 3.33-3.48 (m, 1H), 2.52 (s, 3H), 1.36 (d, J=6.82 Hz, 3H), 1.21-1.33 (m, 3H). HRMS calcd. for C 21 H 21 N 5 (M+H) + 344.1870. found 344.1865.

b) (+) and (−)-2-(Amino(5-isopropyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(amino(5-isopropyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by normal phase chiral HPLC using a CHIRALCEL® OD column with 15% EtOH in heptane to give (+) or (−)-2-(amino(5-isopropyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =10.5 min) and (−) or (+)-2-(amino(5-isopropyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =19.4 min).

(±)-N-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)-2,2,2-trifluoro-N-methylacetamide and (±)-N-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)-2,2,2-trifluoro-N-methylacetamide

To a solution of a mixture of (±)-N-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)-2,2,2-trifluoroacetamide and (±)-N-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)-2,2,2-trifluoroacetamide (Example 95-A) (300 mg, 0.431 mmol) in anhydrous DMF (4 mL), NaH (60% oil dispersion, 22.42 mg, 0.560 mmol) was added at 0° C. After stirring for 15 min at rt, MeI (0.054 mL, 0.862 mmol) was added at 0° C. After stirring for 16 h at rt, the reaction was quenched with aq. NH 4 Cl. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (heptanes/EtOAc=100:0 to 65:35) to give the title compounds as a mixture. MS (ESI+) m/z 710.43 (M+H).

(±)-2-((5,7-Dimethyl-1H-indol-4-yl)(methylamino)methyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from a mixture of (±)-N-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)-2,2,2-trifluoro-N-methylacetamide and (±)-N-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)-2,2,2-trifluoro-N-methylacetamide as described in Example 64-B and 64-C. 1 H NMR (TFA salt, 400 MHz, ACETONITRILE-d 3 ) δ ppm 9.52 (br. s, 1H) 8.00 (s, 1H) 7.54-7.62 (m, 2H) 7.16 (s, 1H) 6.98 (s, 1H) 6.33 (s, 1H) 6.06 (s, 1H) 2.68 (s, 3H) 2.55 (s, 3H) 2.49 (s, 3H). HRMS calcd. for C 20 H 19 N 5 (M+H) + 330.1713. found 330.1716.

(±)-N-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)methanesulfonamide and (±)-N-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)methanesulfonamide

To a solution of a mixture of (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile, (±)-2-((5,7-dimethyl-1-tosyl-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (114 mg, 0.190 mmol), and DBU (0.086 mL, 0.569 mmol) in toluene (1.9 mL), DPPA (0.123 mL, 0.569 mmol) was added at rt. After stirring for 15 h at rt, additional DBU (0.029 mL, 0.190 mmol) and DPPA (0.041 mL, 0.190 mmol) were added. After stirring for 3 h, the reaction mixture was diluted with 2 M aq. Na 2 CO 3 and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layer was washed with 1 M aq. KHSO 4 and then with brine, dried over Na 2 SO 4 , filtered, and concentrated. A solution of the resulting residue was dissolved in EtOH (4 mL) and was hydrogenated by using the H-Cube® apparatus (1 atm, rt, 10% Pd/C, 1 mL/min.) for 1.5 h. The mixture was concentrated and dissolved in CH 2 Cl 2 (1.9 mL) to which DIPEA (0.066 mL, 0.380 mmol) and Ms 2 O (49.6 mg, 0.285 mmol) were added at rt. After stirring for 1 h, additional DIPEA (0.066 mL, 0.380 mmol) and Ms 2 O (49.6 mg, 0.285 mmol) were added. After stirring for 1 h, the mixture was diluted with brine and CH 2 Cl 2 . The layers were separated and the organic layer was collected, dried over MgSO 4 , filtered and concentrated. The residue was purified by flash column chromatography on silica gel (heptanes/EtOAc=100:0 to 30:70) to give the title compounds as a mixture. MS (ESI+) m/z 678.4 (M+H).

(±)-N-((5-cyano-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1H-indol-4-yl)methyl)methanesulfonamide

The title compound was synthesized from a mixture of (±)-N-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)methanesulfonamide and (±)-N-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methyl)methanesulfonamide as described in Example 64-B and 64-C. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.01 (s, 1H) 7.97 (br. s, 1H) 7.58-7.60 (m, 1H) 7.49 (m, 1H) 7.18 (t, J=2.78 Hz, 1H) 6.78 (s, 1H) 6.35-6.37 (m, 2H) 2.82 (s, 3H) 2.44 (s, 3H) 2.42 (s, 3H). HRMS calcd. for C 20 H 19 N 6 O 2 S (M+H) + 394.1332. found 394.1332.

(±)-N-((5-cyano-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1H-indol-4-yl)methyl)acetamide

The title compound was synthesized as described in Example 99 using Ac 2 O in the place of Ms 2 O in Example 99-A. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.96 (s, 1H) 8.71 (d, J=7.33, 1H) 7.99 (br. s, 1H) 7.58 (br. s, 1H) 7.51 (app dd, J=8.34, 1.52 Hz, 1H) 7.12 (app t, J=2.91 Hz, 1H) 6.77 (s, 1H) 6.72 (d, J=7.33 Hz, 1H) 6.05 (dd, J=3.03, 1.77 Hz, 1H) 2.41 (s, 3H) 2.39 (s, 3H) 1.97 (s, 3H). HRMS calcd. for C 21 H 19 N 5 O (M+H) + 358.1663. found 358.1663.

(±)-N-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methylene)-2-methylpropane-2-sulfinamide and (±)-N-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1-tosyl-1H-indol-4-yl)methylene)-2-methylpropane-2-sulfinamide

A suspension of a mixture of 2-(5,7-dimethyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(5,7-dimethyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 75-A) (96 mg, 0.769 mmol), and Ti(O-i-Pr) 4 (1.4 mL, 4.89 mmol) was allowed to stir at 90° C. After stirring for 18 h, the reaction mixture was cooled to rt and diluted with EtOAc and brine. The resulting mixture was filtered and the organic layer of the filtrate was separated. The organic layer was dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (heptanes/EtOAc=100:0 to 30:70) to give title compounds as a mixture. MS (ESI+) m/z 702.54 (M+H).

(±)-N-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide and (±)-N-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of (±)-N-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide and (±)-N-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide (410 mg, 0.584 mmol) in THF (5 mL), MeMgCl (3 M in THF, 0.584 mL, 1.752 mmol) was added the reaction was allowed to stir at rt for 50 min. The mixture was diluted with aq. NH 4 Cl and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated to give title compounds as a mixture. MS (ESI+) m/z 718.73 (M+H).

(±)-N-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide

The title compound was synthesized from a mixture of (±)-N-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide and (±)-N-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide as described in Example 64-B. MS (ESI+) m/z 598.47 (M+H).

(±)-2-(1-Amino-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

A solution of (±)-N-(1-(5-cyanobenzo[d]imidazol-2-yl)-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide (97 mg, 0.165 mmol) and HCl (1.25 M in MeOH) (792 μL, 0.990 mmol) was allowed to stir at rt for 17 h. The mixture was concentrated and then diluted with 1 M aq. NaOH, brine and CH 2 Cl 2 . The organic layer was separated and concentrated. The residue was purified by flash column chromatography on silica gel (CH 2 Cl 2 /MeOH=100:0 to 10:1) to give the title compound. MS (ESI+) m/z 484.44 (M+H).

a) (±)-2-(1-Amino-1-(5,7-dimethyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from (±)-2-(1-amino-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)benzo[d]imidazole-5-carbonitrile as described in Example 64-C. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.78 (s, 1H) 7.91 (s, 1H) 7.53 (br. d, J=8.34 Hz, 1H) 7.41 (br. d, J=7.73 Hz, 1H) 7.09 (t, J=2.78 Hz, 1H) 6.58-6.59 (m, 2H) 2.37 (s, 3H) 1.98 (s, 3H) 1.95 (s, 3H). HRMS calcd. for C 20 H 19 N 6 (M+H) + 330.1713. found 330.1718.

b) (+) and (−)-2-(1-Amino-1-(5,7-dimethyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(1-amino-1-(5,7-dimethyl-1H-indol-4-yl)ethyl)benzo[d]imidazole-5-carbonitrile was achieved by chiral SFC using a CHIRALCEL® OD-H column with 30% MeOH (with 0.2% DEA) in CO 2 to give (+)-2-(1-amino-1-(5,7-dimethyl-1H-indol-4-yl)ethyl)benzo[d]imidazole-5-carbonitrile (t r =1.6 min) and (−)-2-(1-amino-1-(5,7-dimethyl-1H-indol-4-yl)ethyl)benzo[d]imidazole-5-carbonitrile (t r =2.2 min).

(±)-N-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide and (±)-N-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide

A mixture of title compounds was synthesized from a mixture of 2-(5-ethyl-7-methyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(5-ethyl-7-methyl-1-tosyl-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 117-A) analogously to the preparation of Example 101-B. MS (ESI+) m/z 732.7 (M+H).

(±)-2-(1-Amino-1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

A solution of (±)-N-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide and (±)-N-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide (330 mg, 0.451 mmol) in 1M HCl in MeOH (5 mL) was stirred at 60° C. for 6 h. The reaction mixture was neutralized with 5% aq. NaHCO 3 . The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 . The organic phase was successively washed by H 2 O and brine, dried over Na 2 SO 4 , and filtered. After concentration, the residue was purified by silica gel flash column chromatography (CH 2 Cl 2 /EtOH=1/0 to 9/1) to give the title compound. MS (ESI−) m/z 496.4 (M−H).

a) (±)-2-(1-Amino-1-(5-ethyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

The title compound was synthesized from (±)-2-(1-amino-1-(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile as described in Example 64-C. 1 H NMR (400 MHz, ACETONITRILE-d 3 with about 5 μL TFA) δ ppm 9.47 (br. s., 1H), 8.01 (s, 1H), 7.61 (d, J=8.60 Hz, 1H), 7.56 (dd, J=1.50, 8.60 Hz, 1H), 7.20 (t, J=3.00 Hz, 1H), 6.93 (s, 1H), 6.13 (dd, J=2.00, 3.00 Hz, 1H), 2.49-2.60 (m, 1H), 2.47 (d, J=0.76 Hz, 3H), 2.43-2.52 (m, 1H), 2.42 (s, 3H), 0.98 (t, J=7.33 Hz, 3H). HRMS calcd. for C 21 H 21 N 5 (M+H) + 344.1870. found 344.1876.

b) (+) and (−)-2-(1-amino-1-(5-ethyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

Resolution of the enantiomers of 2-(1-amino-1-(5-ethyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile was achieved by normal phase chiral HPLC using a CHIRALCEL® OD column with 15% EtOH to give (+)-2-(1-amino-1-(5-ethyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =12.0 min) and (−)-2-(1-amino-1-(5-ethyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile (t r =15.6 min).

The following compounds were prepared with similar methods.

(±)-2-(1-Amino-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-amino-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile

To a solution of a mixture of (±)-N-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5,7-dim ethyl-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide and (±)-N-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide (280 mg) in anhydrous MeOH (1.07 mL), HCl (1.25 M in MeOH) (0.683 mL, 0.854 mmol) was added at rt. After stirring for 1 h, additional HCl (1.25 M in MeOH) (0.683 mL, 0.854 mmol) was added. After stirring for further 2.5 h, the reaction was diluted with 2 M aq. Na 2 CO 3 , brine and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (heptanes/EtOAc=100:0 to 40:60) to give the mixture of title compounds. MS (ESI+) m/z 614.35 (M+H).

(±)-tert-Butyl (1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)carbamate and (±)-tert-butyl 1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)carbamate

A mixture of (±)-2-(1-amino-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(1-amino-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (153 mg, 0.249 mmol) and Boc 2 O (544 mg, 2.492 mmol) was allowed to stir at 60° C. for 6.5 h. The reaction mixture was cooled to rt, and then purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 65:35) to give the title compounds as a mixture. MS (ESI+) m/z 714.64 (M+H).

(±)-tert-Butyl 1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2